Process for Preparing Pyrido[2,3-d]pyrimidin-7-one and 3,4-Dihydropyrimido[4,5-d]pyrimidin-2(1H)-one Derivatives

ABSTRACT

The present invention is directed to a novel method of preparing of 2,4,8-trisubstituted pyrido[2,3-d]pyrimidin-7-one pharmacophores of Formula (II) or (IIa) 
     
       
         
         
             
             
         
       
     
     wherein
     G1 is CH 2 ;   G2 is CH;   Rx is chloro, bromo, iodo, or O—S(O) 2 CF 3 ;   R g  is a C 1-10  alkyl;   m is 0, or an integer having a value of 1, or 2;   R 3  is a C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclic or a heterocyclylC 1-10  alkyl moiety, and wherein each of these moieties may be optionally substituted.
       which comprises reacting a compound of the formula:   
       

     
       
         
         
             
             
         
       
     
     wherein
     Ry is chloro, bromo, iodo, O—S(O) 2 CF 3 ; and   Rg is a C 1-10  alkyl;
 
with a olefin forming reagent in a suitable base to yield a compound of Formula (II), or (IIa) wherein m=0 and oxidizing the sulphur as necessary or desired.

RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.11/388,375, filed 24 Mar. 2006, (now allowed) which claims the benefitof priority from provisional application U.S. Ser. No. 60/665,154, filed25 Mar. 2005.

FIELD OF THE INVENTION

This invention relates to a novel process to producepyrido[2,3-d]pyrimidin-7-one containing compounds or3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one containing compounds.

BACKGROUND OF THE INVENTION

Preparation of 2,4,8-trisubstituted pyrido[2,3-d]pyrimidin-7-one hasbeen demonstrated by a small, but limited, number of methods. Ingeneral, these methods either include lengthy synthetic sequence (e.g.,more than 5 steps in the longest linear sequence from commerciallyavailable starting materials) or are not conducive for use instructure-activity relationship studies [e.g., not amenable tomulti-dimensional (> or =2-D) array syntheses]. Doherty, J. B. et al.,(Merck, U.S. Pat. No. 6,809,199) discloses an eight-step method toprepare intermediates with structures similar to (II) wherein C4 and N8have already been substituted with phenyl groups. Mauro, A. et al.(Pharmacia, US 2004/0009993) reported a nine-step method to prepareintermediates with structures similar to (II) wherein C4 is substitutedwith C₁-C₆ alkyl or C₁-C₆ arylalkyl and N8 has been connected with aphenyl group. Adams, J. L. et al. (SmithKline Beecham: WO 02/059083; WO03/088972; Tetrahedron Letters, 2003, Vol. 44, pages 4567-4570)discloses a four-step method to prepare intermediates with structuressimilar to (II) wherein the C4 position has already been substituted viaa Suzuki cross coupling reaction and N8 is substituted with alkyl oraryl.

However, despite all of these methods there still remains a need for anefficient method to prepare 2,4,8-trisubstitutedpyrido[2,3-d]pyridine-7-one that can independently optimize thesubstituents at C2 and C4.

SUMMARY OF THE INVENTION

The present invention is directed to the novel compounds of Formula(II):

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;-   R_(g) is a C₁₋₁₀ alkyl;-   m is 0, or an integer having a value of 1, or 2;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted.

The present invention is also directed to a novel process to makecompounds of Formula (II) wherein m=0, which comprises reacting acompound of the formula:

wherein

-   Ry is chloro, bromo, iodo, O—S(O)₂CF₃; and-   Rg is a C₁₋₁₀ alkyl;    with a olefin forming reagent in a suitable base to yield a compound    of Formula (II), wherein G2 is CH, which may optionally be reduced    to a compound of Formula (IIa) under standard reducing conditions if    desired.

The present invention is also directed to the novel compounds of Formula(V)

wherein

-   Ry is bromo, iodo, O—S(O)₂CF₃; and-   Rg is a C₁₋₁₀ alkyl.

The present invention is also directed to novel compounds of Formula(III):

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;-   X is R₂, OR_(2′), S(O)_(m)R_(2′), (CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′),    (CH₂)_(n′)N(R₁₁)C(O)R_(2′), (CH₂)_(n′)NR₄R₁₄, or    (CH₂)_(n′)N(R_(2′))(R_(2″)), or N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R_(1′)), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀-alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or R₂ is the moiety    (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀-alkyl, heterocyclic, or a heterocyclylC₁₋₁₀-alkyl    moiety, and wherein these moieties, excluding hydrogen, may be    optionally substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₀ alkyl, aryl, or    aryl C₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is a C₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₀ alkyl, aryl,    arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic or    a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties    may be optionally substituted;-   R₄ and R₁₄ are each independently selected from hydrogen, C₁₋₁₀    alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₁₄    alkyl, heterocyclic, heterocylic C₁₋₄ alkyl, heteroaryl or a    heteroaryl C₁₋₄ alkyl moiety, and wherein each of these moieties,    excluding hydrogen, may be optionally substituted; or the R₄ and R₁₄    together with the nitrogen which they are attached form an    optionally substituted heterocyclic ring of 4 to 7 members, which    ring optionally contains an additional heteroatom selected from    oxygen, sulfur or nitrogen;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;-   R_(10′) is independently selected at each occurrence from hydrogen    or C₁₋₄alkyl;-   R₁₁ is independently selected from hydrogen or C₁₋₄alkyl;-   n′ is independently selected at each occurrence from 0 or an integer    having a value of 1 to 10;-   m is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6; or-   t is an integer having a value of 2 to 6.

The present invention is also directed to a process for making acompound Formula (III) or (IIIa), which comprises reacting a compound offormula (II) or (IIa)

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;-   Rg is a C₁₋₁₀ alkyl;-   m is an integer having a value of 1, or 2;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic    or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these    moieties may be optionally substituted.    with the compound X—Y,-   wherein X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′), (CH₂)_(n′)N(R₁₁)C(O)R_(2′),    (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′; and R₂, R_(2′), m, n′, R₁₁,    R_(10′), R_(h) and RqRq′ are as defined according to Formula (III)    herein; and    -   Y is hydrogen, a metal, a boronic acid derivative, or a trialkyl        tin derivative, in an anhydrous organic solvent which does not        contain a nucleophile to yield a compound of Formula (III);        provided that    -   when Y is hydrogen then        -   a) X=OR_(2′), or X is S(O)_(m)R_(2′) (and m=0); or        -   b) X is (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′),            (CH₂)_(n′)N(R_(10′))C(O)R_(2′), (CH₂)_(n′)NR₄R₁₄, or            (CH₂)_(n′)N(R_(2′))(R_(2″)) and n′=0; or        -   c) X=R₂ and R₂=(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃),            q′=0, and X₁ is N(R_(10′)), O, S(O)_(m) and m=0.        -   d) when X is N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′; and    -   when Y is a metal, such as Li, Mg, or any other appropriate        metal or metal complexes; then        -   a) X is R₂, and R₂ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇            cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,            heteroaryl C₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀            alkyl moiety; and    -   when Y is a boronic acid, (B(OH)₂) or boronic ester derivatives        -   a) X=R₂, and R₂=aryl, or heteroaryl; and    -   when Y is a trialkyl tin derivative, such as (C₁₋₄ alkyl)₃Sn,        then        -   a) X=R₂, and R₂=aryl, or heteroaryl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an alternative process for preparation ofcompounds having a pyrido[2,3-d]pyrimidin-7-one template or a3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives.

This novel process provides for facile variation of the C4 position inthe both of these templates, and therefore ease of use in the making ofa combinatorial array.

The process as will be described herein provides for different (R₁)substituents to be introduced at the C₄ position of the compounds withthe general structure of Formula I, late in a synthetic sequence afterthe pyrido[2,3-d]pyrimidin-7-one or the3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one template has already beensubstituted with a substituent (“X” in Formula J) at the C₂ position andwith another substituent (“R₃” in Formula I) at the N₈ position.

Generically the reaction is:

wherein W is a leaving group such as chlorine, bromine, iodine,OS(O)CF₃; and R₁, R₃ and X are as defined in Formula (I).

Compounds of Formula (I) are represented by the structure:

wherein

-   G1 is CH₂, or NH:-   G2 is CH or nitrogen;-   R₁ is an aryl, aryl C₂₋₁₀ alkyl, heteroaryl, heteroaryl C₂₋₁₀ alkyl;    aryl C₂₋₁₀ alkenyl, arylC₂₋₁₀ alkynyl, heteroaryl C₂₋₁₀ alkenyl,    heteroaryl C₂₋₁₀ alkynyl, C₂₋₁₀alkenyl, or C₂₋₁₀ alkynyl moiety,    which moieties may be optionally substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or-   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀-alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R_(10′) is independently selected at each occurrence from hydrogen    or C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   n′ is independently selected at each occurrence from 0 or an integer    having a value of 1 to 10;-   m is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6; or    a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Compounds of Formula (I) having a similar template are described in WO01/64679, WO 02/059083, and WO 03/088972 whose disclosures areincorporated by reference in their entirety herein.

It should be noted that the difference between compounds of Formula (I)and (Ia), as well as (II) and (IIa), (III) and (IIIa) lie in theunsaturation of the ring at the C5 position and the 6-position of thering which may be a carbon or a nitrogen. The remaining variables on thering are the same otherwise, e.g. Rx, R₁, R₃, etc. for each formula.Unless otherwise specified, the substitution applicable to Formula (I)is also applicable to Formula (IIa), etc.

For all of the formulas herein having an R₁ substitutent, R₁ is suitablyan aryl, aryl C₂₋₁₀ alkyl, heteroaryl, heteroaryl C₂₋₁₀ alkyl; arylC₂₋₁₀ alkenyl, arylC₂₋₁₀ alkynyl, heteroaryl C₂₋₁₀ alkenyl, heteroarylC₂₋₁₀ alkynyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl moiety, which moietiesmay be optionally substituted.

In one embodiment R₁ is an optionally substituted aryl, or an optionallysubstituted heteroaryl ring. Preferably, R₁ is an optionally substitutedaryl, more preferably an optionally substituted phenyl.

R₁ may be substituted one or more times, suitably 1 to 4 times,independently at each occurrence by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, aryl, arylC₁₋₄ alkyl,(CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅,(CR₁₀R₂₀)_(v′)OR₁₃, (CR₁₀R₂₀)_(v)C(Z)NR₄R₄, (CR₁₀R₂₀)_(v)C(Z)OR₈,(CR₁₀R₂₀)_(v)COR_(a′), (CR₁₀R₂₀)_(v)C(O)H, ZC(Z)R₁₁, N(R_(10′))C(Z)R₁₁,N(R_(10′))S(O)₂R₇, C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b),C(Z)O(CR₁₀R₂₀)_(v)R_(b), N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);N(R₁₀)C(Z)N(R₁₀)(CR₁₀R₂₀)_(v)R_(b); orN(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b).

Suitably, R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀-alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,heteroarylC₁₋₁₀-alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety, which moieties excluding hydrogen, may all be optionallysubstituted.

In one embodiment of the invention when the R₁ moiety is phenyl, and thephenyl ring is substituted by the moiety (R_(1″)) wherein R_(1″) isselected from C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b),N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b),N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), orN(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b). The phenyl ring may also beadditionally substituted by the substituent (R_(1′))g, wherein g is 0 oran integer having a value of 1, 2, 3, or 4. In one embodiment of theinvention, g is 0, 1 or 2. When the R₁ moiety is substituted by R_(1″)then these substituents are preferably in the 3- or 4-position of thephenyl ring.

Suitably, the R_(1′) moiety is independently selected at each occurrencefrom halogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,(CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′) C(O)R₁₂, SR₅, S(O)R₅,S(O)₂R₅, or (CR₁₀R₂₀)_(v′)OR₁₃.

In one embodiment of the invention, R₁ is substituted byC(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), or N(R₁₀)C(Z)(CR₁₀R₂₀)_(v)R_(b), andR_(1′) is independently selected at each occurrence from C₁₋₄ alkyl,such as methyl, or halogen, such as fluorine or chlorine or bromine, orhalo-substituted-C₁₋₄ alkyl, such as CF₃. In a further embodiment R₁ isan aryl moiety, preferably a phenyl ring.

In another embodiment of the invention R₁ is substituted byC(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), and R₁ is independently selected ateach occurrence from C₁₋₄ alkyl, such as methyl, or halogen, such asfluorine, chlorine or bromine.

In one embodiment, R_(1′) is independently selected at each occurrencefrom halogen, C₁₋₄ alkyl, or halo-substituted-C₁₋₄ alkyl. In anotherembodiment, R_(1′) is independently selected at each occurrence fromfluorine, chlorine, methyl, or CF₃. In a further embodiment R₁ is anaryl moiety, preferably a phenyl ring.

In one embodiment, R₁ is an aryl moiety, preferably a phenyl ring,optionally substituted one or more times by halogen, C₁₋₄ alkyl, orhalo-substituted-C₁₋₄ alkyl. More preferably, the phenyl ring issubstituted in the 2, 4, or 6-position, or di-substituted in the2,4-position, such as 2-fluoro, 3-fluoro, 4-fluoro, 2,4-difluoro, or2-methyl-4-fluoro; or tri-substituted in the 2,4,6-position such as2,4,6-trifluoro.

In another embodiment R₁ is an aryl moiety, preferably a phenyl ring,optionally substituted one or more times by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_(v′)OR₁₃,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), and(CR₁₀R₂₀)_(v)C(Z)OR₈. In one embodiment, R₈ is hydrogen, or C₁₋₄ alkyl,R₁₃ is hydrogen, or C₁₋₄ alkyl, such as methyl; R_(b) is suitablyhydrogen, C₁₋₄ alkyl, aryl, or heteroaryl. Preferably, R₁ is a phenylsubstituted by 2-methoxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro,4-chloro, 2-fluoro, 3-fluoro, 4-fluoro, 4-difluoro, 2,4,6-trifluoro,3,4-difluoro, 3,5-difluoro, 2-methyl-4-fluoro, 2-methyl-4-chloro,2-methylsulfanyl, 3-methylsulfanyl, 4-methylsulfanyl, 2-phenyl,3-phenyl, 4-phenyl, 2-methyl, 3-methyl, 4-methyl, 3-fluoro-4-phenyl,2-hydroxy, 3-hydroxy, 4-hydroxy, 2-methylsulfonyl, 3-methylsulfonyl,4-methylsulfonyl, 3-N-cyclopropylamide,2-methyl-3-fluoro-5-N-cyclopropylamide, 2-C(O)OH, 3-C(O)OH, 4-C(O)OH,2-methyl-5-C(O)OH, 2-methyl-3-C(O)OH, 2-methyl-4-C(O)OH,2-methyl-3-F-5-C(O)OH, 4-F-phenyl1-amide, 2-ethyl-5-C(O)OH,2-ethyl-3-C(O)OH, 2-ethyl-4-C(O)OH, 2-methyl-5-dimethylamide,2-methyl-4-dimethylamide, 5-dimethylamide, and 4-dimethylamide.

A preferred R₁ moiety is 4-methyl-N-1,3-thiazol-2-ylbenzamide,N-(4-fluorophenyl)-4-methylbenzamide, 4-methyl-N-propylbenzamide,4-methyl-N-isopropylbenzamide, 2-methyl-4-fluorophenyl, or2-methyl-3-fluorophenyl, and 2-methyl-4-chlorophenyl.

Suitably, when R₁ is a heteroaryl moiety, the ring is not attached tothe pharmacophore via one of the heteroatoms, such as nitrogen to form acharged ring. For instance, a pyridinyl ring would be attached through acarbon atom to yield a 2-, 3- or 4-pyridyl moiety, which is optionallysubstituted.

If R₁ is substituted by C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b),C(Z)O(CR₁₀R₂₀)_(v)R_(b), or N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);N(R₁₀)C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b);N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b); it is preferably in the 4 or 5position of the ring. If the ring is additionally substituted by R_(1′),and R₁ is a phenyl ring, then the additional substituents are present inthe ortho position, if a second R_(1′) moiety is also substituted on thering, then preferably, this second R_(1′) substitution is not in theother ortho position.

Suitably, R_(a′) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)N(R_(10′))S(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein thearyl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionallysubstituted.

Suitably, R_(d) and R_(d′) are each independently selected fromhydrogen, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylC₁₋₄alkyl, or theR_(d) and R_(d′) together with the nitrogen which they are attached forman optionally substituted heterocyclic ring of 5 to 6 members, whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR_(9′), and wherein the R_(d) and R_(d′) moieties which areC₁₋₄ alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄ alkyl, and the R₄ and R₁₄cyclized ring are optionally substituted, 1 to 4 times, independently byhalogen; halosubstituted C₁₋₄ alkyl; hydroxy; hydroxy substitutedC₁₋₁₄alkyl; C₁₋₄ alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)_(m)Rf;C(O)Rj; C(O)ORj; C(O)NR_(4′)R_(14′), NR_(4′)C(O)C₁₋₄alkyl;S(O)₂NR_(4′)R_(14′)C₁₋₄ alkyl; NR_(4′)R_(14′)S(O)₂C₁₋₄ alkyl; orNR_(4′)R_(14′).

Suitably R_(9′) is independently selected at each occurrence fromhydrogen, or C₁₋₄ alkyl.

Suitably, Z is independently at each occurrence selected from oxygen orsulfur.

Suitably, m is independently selected at each occurrence from 0 or aninteger having a value of 1 or 2.

Suitably, v is 0 or an integer having a value of 1 to 2.

Suitably, v′ is 0 or an integer having a value of 1 or 2.

Suitably, R₁₀ and R₂₀ are independently selected at each occurrence fromhydrogen or C₁₋₄ alkyl.

Suitably, R_(10′) is independently selected at each occurrence fromhydrogen or C₁₋₄ alkyl.

Suitably, R₁₁ is independently selected at each occurrence fromhydrogen, or C₁₋₄ alkyl.

Suitably, R₁₂ is independently selected at each occurrence fromhydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl, andwherein these moieties, excluding hydrogen, may be optionallysubstituted.

Suitably, R₁₃ is independently selected at each occurrence fromhydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl moiety,and wherein each of these moieties, excluding hydrogen, may beoptionally substituted and wherein these moieties, excluding hydrogen,may be optionally substituted 1 to 4 times by halogen; halosubstitutedC₁₋₄ alkyl; C₁₋₄ alkyl; hydroxy; hydroxy substituted C₁₋₄alkyl;C₁₋₄alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)_(m)C₁₋₄ alkyl; —C(O),C(O)C₁₋₄ alkyl; or NR_(21′)R_(31′).

Suitably, R_(21′) and R_(31′) are each independently selected fromhydrogen or C₁₋₄ alkyl, or R_(21′) and R_(31′) together with thenitrogen to which they are attached cyclize to form a 5 to 7 memberedring which optionally contains an additional heteroatom selected fromoxygen, nitrogen or sulfur.

The R_(b) moieties, excluding hydrogen, may be optionally substituted,one or more times, preferably 1 to 4 times independently at eachoccurrence by halogen, such as fluorine, chlorine, bromine or iodine;hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, such as methoxyor ethoxy; halosubstituted C₁₋₁₀ alkoxy; OR₈, such as methoxy, ethoxy orphenoxy; SR₅, S(O)R₅, S(O)₂R₅, such as methyl thio, methylsulfinyl ormethyl sulfonyl; C(O)R_(j); C(O)OR_(j); C(O)NR_(4″)R_(14″); cyano;nitro; NR₁₅R₂₅; -Z′-(CR₁₀R₂₀)_(s)-Z′; C₁₋₁₀alkyl; such as methyl, ethyl,propyl, isopropyl, t-butyl, n-butyl, etc.; C₃₋₇cycloalkyl or aC₃₋₇cycloalkyl C₁₋₁₀ alkyl group, such as cyclopropyl, or cyclopropylmethyl, or cyclopropyl ethyl, etc.; halosubstituted C₁₋₁₀ alkyl, suchCF₂CF₂H, CH₂CF₃, or CF₃; an optionally substituted aryl, such as phenyl,or an optionally substituted aryl C₁₋₁₀alkyl, such as benzyl orphenethyl; an optionally substituted heterocyclic or heterocyclic C₁₋₁₀alkyl, or an optionally substituted heteroaryl or heteroaryl C₁₋₁₀alkyl,and wherein these aryl, heteroaryl, and heterocyclic containing moietiesmay also be substituted one to two times by halogen, hydroxy, hydroxysubstituted alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono &di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, when R_(b) is an optionally substituted C₁₋₁₀alkyl, the moietyincludes but is not limited to a methyl, ethyl, n-propyl, isopropyl,t-butyl, n-butyl, isobutyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,heptyl, 2-methylpropyl; a halosubstituted alkyl, such as2,2,2-trifluoroethyl, trifluoromethyl, 2-fluoroethyl; a cyanosubstituted alkyl, such as cyanomethyl, cyanoethyl; an alkoxy, thio orhydroxy substituted alkyl, such as 2-methoxy-ethyl, 2-hydroxy propyl orserinol, or an ethylthioethyl.

In an alternative embodiment, when R_(b) is an optionally substitutedC₁₋₁₀alkyl the moiety is a methyl, ethyl, n-propyl, isopropyl, t-butyl,n-butyl, or 2,2-dimethylpropyl or 2-hydroxy propyl group.

Suitably, when R_(b) is an optionally substituted heteroaryl, heteroarylalkyl they are as defined in the definition section, and include but arenot limited, to furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil, indolyl,isoindolyl, indazolyl, indolizinyl, azaindolyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl,purinyl, and phthalazinyl.

Suitably, when R_(b) is an optionally substituted heterocyclic,heterocyclic alkyl, they are as defined in the definition section,

In one embodiment of the invention, when R_(b) is an optionallysubstituted heteroaryl, heteroaryl alkyl, heterocyclic or heterocyclicalkyl, the moiety is a 1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl,isoquinoline, 3-thiophene, indol-5-yl, pyridin-3-yl, pyridine-4-yl,indazolyl, benzothiazolyl, 2-methyl-1,3-benzothiazol-5-yl, pyrazol-3-yl,4-morpholino, 2-furanyl, 2-furanylmethyl, 2-thienyl, 2-thienylmethyl,tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl methyl,tetrahydro-2-furanyl, or tetrahydro-2-furanylmethyl, 1H-imidazol-4-yl or1H-imidazol-4-ylethyl.

In an alternative embodiment, when R_(b) is an optionally substitutedheteroaryl the moiety is a 1,3-thiazol-2-yl or5-methyl-1,3-thiazol-2-yl, isoquinolinyl, thiophene, pyridinyl,indazolyl, benzothiazolyl, e.g. 2-methyl-1,3-benzothiazol-5-yl.

In another embodiment, the heteroaryl ring is an optionally substitutedthiazolyl, pyridyl, or thiophene ring.

Suitably, when R_(b) is an optionally substituted aryl or arylalkylmoiety, the aryl containing is unsubstituted or substitutedindependently at each occurrence one or more times by halogen, alkyl,cyano, OR₈, SR₅, S(O)₂R₅, C(O)R_(j), C(O)OR_(j), -Z′-(CR₁₀R₂₀)_(s)-Z′,halosubstituted C₁₋₁₀ alkyl, or an optionally substituted aryl.

In one embodiment, R_(b) is a phenyl, or napthylene, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,3-difluorphenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-chloro-4-fluorophenyl, 2-methyl phenyl, 3-methylphenyl,4-methylphenyl, 6-methyl phenyl, 2-methyl phenyl, 3-amino phenyl,3,4-dimethyl phenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl,4-ethoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl,4-thiomethylphenyl, 4-acetylphenyl, 4-dimethylaminophenyl, benzyl,phenethyl, phenylpropyl, 2,3-difluoro-benzyl, 3,5-difluoro-benzyl,biphenyl, 4′-fluorobiphenyl, 4-sulfonamindo-2-methylphenyl, or3-phenyloxyphenyl, 4-phenyloxyphenyl, 4-(1-piperidinylsulfonyl)-phenyl,or 3-(aminocarbonyl)phenyl.

In another embodiment, R_(b) is a phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-chloro-4-fluorophenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl,2-methylphenyl, 3-methylphenyl, 4-ethoxyphenyl, 4-methoxyphenyl,3-cyanophenyl, 4-cyanophenyl, 4-thiomethylphenyl, 4-acetylphenyl,4-dimethylaminophenyl, biphenyl, 4′-fluorobiphenyl,4-sulfonamindo-2-methylphenyl, 3-phenyloxyphenyl, benzyl, or phenethyl.

Suitably, when R_(b) is an optionally substituted cycloalkyl orcycloalkyl alkyl moiety, the moiety is a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, or a cyclopentylmethyl. Inanother embodiment, R_(b) is a cyclopropyl or cyclopropylmethyl group.

In another embodiment, R_(b) is hydrogen, or an optionally substitutedalkyl.

In another embodiment, R_(b) is C₁₋₁₀ alkyl, heteroaryl, or aryl, alloptionally substituted.

The moiety -Z′-(CR₁₀R₂₀)_(s)-Z′ forms a cyclic ring, such as a dioxalanering.

Suitably Z′ is independently selected at each occurrence from oxygen, orsulfur.

Suitably, R₅ is independently selected at each occurrence from 0 or aninteger having a value of 1, 2, or 3.

For each of the integer variables where appropriate, e.g. n, n′, m, q′,s, t, or v′, etc. they are independently chosen at each occurrence.

Suitably, R₅ is independently selected at each occurrence from hydrogen,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding themoieties SR₅ being SNR_(4′)R_(14′), S(O)₂R₅ being SO₂H and S(O)R₅ beingSOH.

Suitably, R_(f) is hydrogen, C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl,heteroaryl, heteroaryl C₁₋₁₀alkyl, heterocyclic, or a heterocyclicC₁₋₁₀alkyl moiety, and wherein these moieties, excluding hydrogen, maybe optionally substituted.

Suitably, R_(j) is C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl,heteroaryl C₁₋₁₀alkyl, heterocyclic, or a heterocyclic C₁₋₁₀alkylmoiety.

Suitably, R₈ is independently selected at each occurrence from hydrogen,C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl moiety,and wherein these moieties, excluding hydrogen, may be optionallysubstituted independently at each occurrence, 1 to 4 times, by halogen;halosubstituted C₁₋₄ alkyl; C₁₋₄ alkyl; C₃₋₅cycloalkyl; C₃₋₅cycloalkylC₁₋₄alkyl; halosubstituted C₁₋₄ alkyl; hydroxy; hydroxy substitutedC₁₋₁₄alkyl; C₁₋₁₄alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)_(m)C₁₋₄alkyl; —C(O), C(O)C₁₋₄ alkyl; NR_(21′)R_(31′); or an aryl or aryl C₁₋₄alkyl, and wherein these aryl containing moieties may also besubstituted one to two times independently at each occurrence, byhalogen, hydroxy, hydroxy substituted alkyl, C₁₋₄ alkoxy,S(O)_(m)C₁₋₄alkyl, amino, mono & di-substituted C₁₋₄ alkylamino, C₁₋₄alkyl, or CF₃.

Suitably, R₁₅ and R₂₅ are each independently selected at each occurrencefrom hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄-alkyl,aryl, or aryl-C₁₋₄ alkyl, heteroaryl or heteroaryl C₁₋₄ alkyl moiety,and wherein these moieties, excluding hydrogen may be optionallysubstituted; or R₁₅ and R₂₅ together with the nitrogen which they areattached form an optionally substituted heterocyclic ring of 4 to 7members, which ring optionally contains an additional heteroatomselected from oxygen, sulfur or NR₉; and wherein these moieties areoptionally substituted 1 to 4 times, independently at each occurrence byhalogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy;halosubstituted C₁₋₁₀ alkoxy; SR₅, S(O)R₅, S(O)₂R₅; C(O)R_(j);C(O)OR_(j); C(O)NR_(4′)R_(14′); NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl;NR_(4′)R_(14′); cyano; nitro; C₁₋₁₀ alkyl; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; aryl, arylC₁₋₄alkyl, heteroaryl, or heteroC₁₋₄ alkyl, heterocyclic andheterocyclicC₁₋₄ alkyl and wherein these aryl, heterocyclic andheteroaryl containing moieties may also be substituted one to two timesindependently at each occurrence by halogen, C₁₋₄ alkyl, hydroxy,hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono& di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R₄ and R₁₄ are each independently selected at each occurrencefrom hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,aryl, aryl-C₁₋₁₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,heteroaryl or heteroaryl C₁₋₄ alkyl; or the R₄ and R₁₄ together with thenitrogen which they are attached form an unsubstituted or substitutedheterocyclic ring of 4 to 7 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or nitrogen; andwherein the C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, aryl,aryl-C₁₋₄ alkyl, heteroaryl and heteroaryl C₁₋₄ alkyl moieties, and theR₄ and R₁₄ cyclized ring are optionally substituted, 1 to 4 times,independently at each occurrence, by halogen; hydroxy; hydroxysubstituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; C₁₋₁₀alkyl; halosubstituted C₁₋₁₀alkyl; SR₅; S(O)R₅; S(O)₂R₅; C(O)R_(j);C(O)OR_(j); C(O)NR_(4′)R_(14′); (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); NR_(4′)C(O)C₁₋₁₀alkyl;NR_(4′)C(O)aryl; NR_(4′)R_(14′); cyano; nitro; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀alkyl; C₁₋₁₀alkyl substituted one or more times byan optionally substituted aryl; an unsubstituted or substituted aryl, orarylC₁₋₄ alkyl; an unsubstituted or substituted heteroaryl, orheteroaryl C₁₋₄ alkyl; an unsubstituted or substituted heterocyclic, orheterocyclic C₁₋₄ alkyl, and wherein these aryl, heterocyclic andheteroaryl containing moieties are substituted one to two timesindependently at each occurrence by halogen; C₁₋₄ alkyl, hydroxy;hydroxy substituted C₁₋₄ alkyl; C₁₋₄ alkoxy; S(O)_(m)alkyl; amino, mono& di-substituted C₁₋₄ alkyl amino, or CF₃.

Suitably, when R₄ and R₁₄ together with the nitrogen cyclize to form anoptionally substituted ring, such as described above, such ringsinclude, but are not limited to pyrrolidine, piperidine, piperazine,diazepine, azepine, morpholine, and thiomorpholine (including oxidizingthe sulfur).

Suitably, R_(4′) and R_(14′) are each independently selected at eachoccurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′) cancyclize together with the nitrogen to which they are attached to form anoptionally substituted 5 to 7 membered ring which optionally contains anadditional heteroatom from oxygen, sulfur or NR_(9′). Suitably, whenR_(4′) and R_(14′) cyclize to form an optionally substituted ring, suchrings include, but are not limited to pyrrolidine, piperidine,piperazine, morpholine, and thiomorpholine (including oxidizing thesulfur).

Suitably, R_(4″) and R_(14″) are each independently selected fromhydrogen or C₁₋₁₀ alkyl, or R_(4″) and R_(14″) can cyclize together withthe nitrogen to which they are attached to form an optionallysubstituted 5 to 7 membered ring which optionally contains an additionalheteroatom selected from oxygen, sulfur or NR_(9′). Suitably, whenR_(4″) and R₁₄ cyclize to form an optionally substituted ring, suchrings include, but are not limited to pyrrolidine, piperidine,piperazine, diazepine, azepine, morpholine, and thiomorpholine(including oxidizing the sulfur).

Suitably, R₆ is independently selected from hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₀ alkyl,heteroaryl or a heteroaryl C₁₋₁₀ alkyl moiety, and wherein thesemoieties, excluding hydrogen may be optionally substitutedindependently, one or more times, suitably 1 to 2 times, by halogen;hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstitutedC₁₋₁₀ alkoxy; S(O)_(m) alkyl; C(O); NR_(4′)R_(14′); C₁₋₁₀ alkyl;C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl;an unsubstituted aryl or arylalkyl, or an aryl or arylalkyl substitutedone or two times by halogen, hydroxy, hydroxy substituted alkyl, C₁₋₁₀alkoxy, S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄ alkyl amino,C₁₋₄ alkyl, or CF₃.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl.The alkyl, aryl and arylalkyl moieties may be optionally substituted 1or 2 times, independently by halogen; hydroxy; hydroxy substitutedC₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)_(m) alkyl;—C(O); NR_(4′)R_(14′); C₁₋₁₀ alkyl, C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀alkyl; halosubstituted C₁₋₁₀ alkyl; an aryl or aryl C₁₋₄ alkyl, andwherein these aryl containing moieties may also be substituted one ortwo times independently by halogen, hydroxy, hydroxy substituted alkyl,C₁₋₁₀ alkoxy, S(O)_(m)C₁₋₁₄ alkyl, amino, mono & di-substituted C₁₋₄alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀alkyl, aryl, arylC₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,heterocyclic, or heterocyclylC₁₋₁₀ alkyl moiety, which moieties may beoptionally substituted 1 to 4 times, independently at each occurrence byhydrogen, halogen, nitro, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl C₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂ NR₁₆R₂₆, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₁₆R₂₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′))NR₁₆R₂₆, (CR₁₀R₂₀)_(n)OC(Z)NR₁₆R₂₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR₁₆R₂₆, or (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In one embodiment, the R₃ moieties are optionally substituted 1 to 4times, independently at each occurrence by halogen, nitro, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₄ alkyl, C₅₋₆cycloalkenyl, C₅₋₆cycloalkenylC₁₋₄ alkyl,(CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)S(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_(n)NR₁₆R₂₆,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆, or(CR₁₀R₂₀)_(n)C(Z)NR₁₆R₂₆.

In one embodiment the R₃ moieties are optionally substitutedindependently, one or more times, suitably 1 to 4 times, independentlyat each occurrence by halogen, C₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₆, cyano,nitro, (CR₁₀R₂₀)_(n)NR₁₆R₂₆, or halosubstituted C₁₋₁₀alkyl. Further tothis embodiment, R₃ is a phenyl ring, optionally substitutedindependently, one or more times, suitably 1 to 4 times, independentlyat each occurrence by halogen, C₁₋₁₀ alkyl, hydroxy, C₁₋₁₀ alkoxy,cyano, nitro, amino, or halosubstituted C₁₀ alkyl. In anotherembodiment, the R₃ substituents are selected independently from halogen,such as fluorine, chlorine, bromine or iodine, or C₁₋₁₀ alkyl, such asmethyl.

In one embodiment the R₃ moieties are an optionally substituted C₁₋₁₀alkyl, optionally substituted C₃₋₇cycloalkyl, optionally substitutedC₃₋₇cycloalkylalkyl, or optionally substituted aryl. In anotherembodiment, the R₃ moiety is an optionally substituted C₁₋₁₀ alkyl, oran optionally substituted aryl. In another embodiment, R₃ is anoptionally substituted phenyl.

Suitably, in one embodiment when R₃ is an aryl moiety, it is anoptionally substituted phenyl ring. The phenyl is optionally substitutedone or more times, independently at each occurrence, suitably 1 to 4times by halogen, C₁₋₄ alkyl, or halo-substituted-C₁₋₄ alkyl. The phenylring may be substituted in the 2, 4, or 6-position, or di-substituted inthe 2,4-position or 2,6-position, such as 2-fluoro, 4-fluoro,2,4-difluoro, 2,6-difluoro, or 2-methyl-4-fluoro; or tri-substituted inthe 2,4,6-position, such as 2,4,6-trifluoro.

In one embodiment of the invention, the R₃ optional substituents areindependently selected from halogen, alkyl, hydroxy, alkoxy, cyano,nitro, amino, or halosubstituted alkyl. In another embodiment, theoptional substituents are independently selected from halogen, or alkyl.

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and whereineach of these moieties may be optionally substituted one or two timesindependently, by halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl;C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)_(m) alkyl; C(O);NR₄R_(14′); C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkylC₁₋₁₀alkyl;halosubstituted C₁₋₁₀ alkyl; an aryl or arylalkyl moiety, and whereinthese aryl containing moieties may also be substituted one to two timesby halogen, hydroxy, hydroxy substituted alkyl, C₁₋₁₀ alkoxy,S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄ alkyl amino, C₁₋₄alkyl, or CF₃.

Suitably, R₁₆ and R₂₆ are each independently selected from hydrogen, orC₁₋₄ alkyl; or the R₁₆ and R₂₆ together with the nitrogen which they areattached form an unsubstituted or substituted heterocyclic ring of 4 to7 members, which ring optionally contains an additional heteroatomselected from oxygen, sulfur or NR_(9′).

Suitably, n is 0 or an integer having a value of 1 to 10, and isindependently selected at each occurrence.

Suitably, X is R₂, OR_(2″), S(O)_(m)R_(2′),(CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′), (CH₂)_(n′)N(R₁₁)C(O)R_(2′),(CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2″))(R_(2″)), orN(R_(10′))R_(h)NH—C(═N—CN)NRqRq′.

Suitably, n′ is independently selected at each occurrence from 0 or aninteger having a value of 1 to 10;

Suitably, R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,—CH₂CH₂—O—CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,—CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂—, —CH₂—C(O)O—CH₂—CH₂—, or—CH₂—CH₂—O—C(O)CH₂—.

Suitably, R_(q) and R_(q′) are independently selected from hydrogen,C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀-alkyl,heteroaryl, heteroarylC₁₋₁₀-alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, wherein all of the moieties are optionally substituted, orR_(q) and R_(q′) together with the nitrogen to which they are attachedform a 5 to 7 membered optionally substituted ring, which ring maycontain an additional heteroatom selected from oxygen, nitrogen orsulphur.

Suitably, X₁ is N(R_(10′)), O, S(O)_(m), or CR₁₀R₂₀. In one embodimentof the invention, X₁ is N(R_(10′)), or O.

Suitably, R₂ is independently selected from hydrogen, optionallysubstituted C₁₋₁₀ alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted C₃₋₇cycloalkylalkyl, optionally substituted aryl,optionally substituted arylC₁₋₁₀alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl C₁₋₁₀ alkyl, optionallysubstituted heterocyclic, optionally substituted heterocyclyl C₁₋₁₀alkylmoiety; or R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃),or (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃).

Suitably q′ is 0, or an integer having a value of 1 to 6.

Suitably q is 0, or an integer having a value of 1 to 10.

The R₂ moieties, excluding hydrogen, may be optionally substituted oneor more times, preferably 1 to 4 times, independently at each occurrenceby C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl,C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, aryl, arylC₁₋₁₀ alkyl, heterocyclic, heterocyclic C₁₋₁₀ alkyl, heteroaryl,heteroaryl C₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇,(CR₁₀R₂₀)_(n)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′),(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z) NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR_(e)R_(e′),(CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z) NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

Suitably, R_(e) and R_(e′) are each independently selected at eachoccurrence from hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₁₄ alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, which moietiesmay be optionally substituted; or R_(e) and R_(e′) together with thenitrogen which they are attached form an optionally substitutedheterocyclic ring of 4 to 7 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or nitrogen; andwherein each of these moieties, including the cyclized ring andexcluding hydrogen, may be substituted 1 to 4 times, independently ateach occurrence by halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl;C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; C₁₋₁₀ alkyl; halosubstitutedC₁₋₄ alkyl; S(O)_(m)R_(f′); C(O)R_(j); C(O)ORj;(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′);C(O)NR₄R_(14′); NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl; cyano; nitro;C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstitutedC₁₋₁₀ alkyl; aryl, arylC₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,heteroaryl, or hetero C₁₋₄ alkyl, and wherein these aryl, heterocyclicor heteroaryl containing moieties may be optionally substituted one totwo times independently at each occurrence by halogen, C₁₋₄ alkyl,hydroxy, hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl,amino, mono & di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R_(f′) is independently selected at each occurrence fromhydrogen, C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, heterocyclic C₁₋₁₀alkyl or NR_(4′)R_(14′), andwherein these moieties, excluding hydrogen, and NR_(4′)R_(14′), may beoptionally substituted.

In one embodiment of the present invention X is R₂, OR_(2′),(CH₂)_(n′)NR₄R₁₄, or (CH₂)_(n′)N(R_(2′))(R_(2″)). In another embodimentof the present invention, X is R₂, and R₂ is (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃).

When X is R₂ and R₂ is an optionally substituted heterocyclic orheterocyclic alkyl, the heterocyclic containing moiety is suitablyselected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran,tetrahydrothiophene (including oxidized versions of the sulfur moiety),aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl,3-oxo-1-pyrrolidinyl, 1,3-benzodioxol-5-yl, imidazolinyl,imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholino and thiomorpholino (including oxidized versionsof the sulfur moiety).

In one embodiment, R₂ is an optionally substituted piperidinyl orpiperazinyl ring.

In another embodiment, when R₂ is an optionally substituted heterocyclicor heterocyclic alkyl ring the ring is substituted one or mores timesindependently by an optionally substituted heterocyclic, heterocyclicalkyl, aryl, arylalkyl, alkyl, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇. The second heterocyclic ring is suitablyselected from an optionally substituted tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl,pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl,1,3-benzodioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine,morpholino or thiomorpholino (including oxidized versions of the sulfurmoiety). Suitably, the second heterocyclic ring is selected frommorpholino, piperidine, or pyrrolidinyl.

In one embodiment, R₂ is a 4-amino-1-piperidinyl,1,1-dimethylethyl)oxy]-carbonyl}amino)-1-piperidinyl,4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl,4-butyl-1-piperazinyl, 4-(methylamino)-1-piperidinyl,1,1-dimethylethyl-4-piperidinyl}methylcarbamate, 4-phenyl-1-piperazinyl,1,4′-bipiperidin-1′-yl, 4-(1-pyrrolidinyl)-1-piperidinyl,4-methyl-1,4′-bipiperidin-1′-yl, 4-(4-morpholinyl)-1-piperidinyl,4-(diphenylmethyl)-1-piperazinyl, or4-methylhexahydro-1H-1,4-diazepin-1-yl.

Suitably, R_(2′) is independently selected at each occurrence fromhydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl,arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or aheterocyclyl C₁₋₁₀alkyl moiety, and wherein each of these moieties,excluding hydrogen, may be optionally substituted 1 to 4 times,independently, at each occurrence, by C₁₋₁₀ alkyl, halo-substitutedC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀-alkyl, halogen, —C(O), cyano, nitro, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀-alkyl, heterocyclic,heterocyclylC₁₋₁₀-alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇,(CR₁₀R₂₀)_(n)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z) NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In one embodiment, when X is (CH₂)_(n)N(R_(2′))(R_(2″)), one of R_(2′)or R₂″, is hydrogen, or methyl.

In one embodiment, when R_(2′) is an optionally substituted heterocyclicor heterocyclylC₁₋₁₀ alkyl the heterocyclic containing moiety issubstituted one or more time independently by C₁₋₁₀ alkyl, aryl,heterocyclic, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇,or (CR₁₀R₂₀)_(n)C(Z)OR₆. More specifically, methyl, ethyl, NHC(O)O—CCH₃,N(CH₃)C(O)O—CCH₃, amino, methylamino, dimethylamino, phenyl, piperidine,pyrrolidine, 1-ethylpropyl, 4-methyl-1,4′-bipiperidin-1′-yl,1,4′-bipiperidin-1′-yl, morpholino,

In one embodiment, when X is (CH₂)_(n)N(R_(2′))(R_(2″)), R_(2′) is anoptionally substituted C₁₋₁₀ alkyl, cycloalkyl, heterocyclic,heterocyclyl C₁₋₁₀ alkyl, heteroarylalkyl. Suitably, when R_(2′) is anoptionally substituted cycloalkyl it is an a cyclohexyl ring. In oneembodiment the cyclohexyl ring is optionally substituted one or moretimes by (CR₁₀R₂₀)_(n)NR_(e)R_(e′).

Suitably, when R_(2′) is an optionally substituted heterocyclic, or aheterocyclylC₁₋₁₀ alkyl, the ring is selected from tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl,pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl,1,3-benzodioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine,hexahydro-1-H-azepine, morpholino or thiomorpholino (including oxidizedversions of the sulfur moiety). Preferably, the ring is a piperidine,piperazine, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, morpholino,hexahydro-1-H-azepine ring. In one embodiment, the rings are substitutedone or more times, suitably 1 to 4 times, independently by C₁₋₁₀ alkyl,aryl, arylalkyl, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In one embodiment, (CH₂)_(n)N(R_(2′))(R_(2″)) is1-(phenylmethyl)-4-piperidinamine,2-[4-(phenylmethyl)-1-piperazinyl]ethylamine,2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine,1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine,3-[(hexahydro-1H-azepin-1-yl)propyl]amine,(1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine,3-[(2-oxo-1-pyrrolidinyl)propyl]-amine, 2-[(4-morpholinyl)ethyl]amine,2-[(1-pyrrolidinyl)ethyl]-amine, or[(1-ethyl-2-pyrrolidinyl)methyl]amino.

In one embodiment when X is (CH₂)_(n)N(R_(2′))(R_(2″)), and R_(2′) is anoptionally substituted C₁₋₁₀alkyl, the alkyl is substituted one or moretimes independently by (CR₁₀R₂₀)_(n)NR_(e)R_(e′) or(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′). In one embodiment R_(e)and R_(e′) are independently an optionally substituted C₁₋₄ alkyl, suchas methyl, ethyl, isopropyl, n-butyl, or t-butyl. Preferably,(CH₂)_(n)N(R_(2′))(R_(2″)) is 3-(dimethylamino)propyl(methyl)amine,3-(diethylamino)propylamine, propylamine, (2,2-dimethylpropyl)amine,(2-hydroxypropyl)amino, 2-(dimethylamino)ethylamine,2-(dimethylamino)ethyl(methyl)amine, 3-(dimethylamino)propylamine,2-(dimethylamino)ethyl(methyl)amine, 3-(diethylamino)propylamine,2-(methylamino)ethylamine, [(1-methylethyl)amino]ethylamine,3-(diethylamino)propylamine, 3-(dibutylamino)propylamine,3-[(1-methylethyl)amino]propylamine,3-(1,1-dimethylethyl)aminopropylamine,3-(dimethylamino)-2,2-dimethylpropylamine,4-(diethylamino)-1-methylbutylamine, or3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine.

Suitably R_(2″) is selected from hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀-alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety, and wherein these moieties, excluding hydrogen, may beoptionally substituted 1 to 4 times, independently at each occurrence,by C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl,C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic,heterocyclyl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇,(CR₁₀R₂₀)_(n)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂ NR_(e)R_(e′),(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)) NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; or wherein R_(2″) is the moiety(CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);

Suitably, t is an integer having a value of 2 to 6.

Suitably, q is 0 or an integer having a value of 1 to 10.

Suitably, A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl, oraryl C₁₋₁₀ alkyl.

Suitably, A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl, oraryl C₁₋₁₀ alkyl.

Suitably, A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl.

The A₁, A₂, and A₃ C₁₋₁₀ alkyl moieties may optionally substituted oneor more times independently at each occurrence, preferably from 1 to 4times, with halogen, such as chlorine, fluorine, bromine, or iodine;halo-substituted C₁₋₁₀alkyl, such as CF₃, or CHF₂CF₃; C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)N(R_(10′))C(z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′))NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In another embodiment of the present invention, X is R₂, and R₂ is(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or(CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃). In a further embodiment, q′ is 0.

In another embodiment when R₂ is the moiety(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), q′ is 0, X₁ is nitrogen, qis 0 or 1, A₁ is an optionally substituted heterocyclic or heterocyclicalkyl, and A₂ is an optionally substituted aryl. More specifically, R₂is 2-phenyl-2-(1-pyrrolidinyl)ethyl]amino, or1-phenyl-2-(1-pyrrolidinyl)ethyl]amino. In another embodiment, A₁ is anoptionally substituted aryl or arylalkyl, and A₂ is an optionallysubstituted aryl or arylalkyl.

In one embodiment of the invention, one or more of the A₁, A₂ and A₃moieties are substituted with (CR₁₀R₂₀)_(n)OR₆—In another embodiment ofthe invention, the R₆ substituent Fin (CR₁₀R₂₀)_(n)OR₆ is hydrogen.

In yet another embodiment of the present invention, X is R₂ and R₂ isC(A₁)(A₂)(A₃), such as CH(CH₂OH)₂, or C(CH₃)(CH₂OH)₂; orX₁(CR₁₀R₂₀)_(q)CH(CH₂OH)₂, or XI (CR₁₀R₂₀)_(q)C(CH₃)(CH₂OH)₂; andfurther wherein X₁ is oxygen or nitrogen.

In another embodiment X is S(O)_(m)R_(2′), (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n)N(R₂)(R_(2′)). In yet another embodiment, X is (CH₂)_(n)NR₄R₁₄,or (CH₂)_(n)N(R₂)(R_(2′)).

Suitably, when X is (CH₂)_(n)NR₄R₁₄, and R₄ and R₁₄ are C₁₋₁₀ alkyl,aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heteroarylor heteroaryl C₁₋₄ alkyl, the C₁₋₄ alkyl may be substituted one or moretimes, independently at each occurrence with NR_(4′)R_(14′); halogen,hydroxy, alkoxy, C(O)NR_(4′)R_(14′); or NR₄C(O) C₁₋₁₀alkyl. Preferably,the C₁₋₄ alkyl is substituted with NR_(4′)R_(14′).

In one embodiment at least one of R₄ and R₁₄ may be hydrogen when R₄ andR₁₄ are not cyclized. In another embodiment neither R₄ nor R₁₄ ishydrogen.

In one embodiment when X is (CH₂)_(n)NR₄R₁₄, one of R₄ and R₁₄ arehydrogen, and the other is an optionally substituted heteroaryl C₁₋₄alkyl. Suitably, the optionally substituted heteroaryl alkyl is animidazolyl alkyl, such as a 1H-imidazol-2-yl-methyl group.

In one embodiment when X is (CH₂)_(n)NR₄R₁₄ and one of R₄ and R₁₄ is aheteroaryl C₁₋₄ alkyl moiety, then the heteroaryl ring is selected fromthienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzoxazolyl, benzimidazolyl, and benzothiazolyl. Suitably, theheteroaryl C₁₋₄ alkyl is selected from pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, imidazolyl, benzoxazolyl, benzimidazolyl, andbenzothiazolyl.

In another embodiment when X is (CH₂)_(n)NR₄R₁₄ and one of R₄ and R₁₄ isa heterocyclic C₁₋₄ alkyl moiety, then the heterocyclic ring is selectedfrom tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl,pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, piperazinyl, and morpholino. Suitably, theheterocyclic C₁₋₄ alkyl moiety is selected from pyrrolinyl,pyrrolidinyl, piperidinyl, piperazinyl, and morpholino.

In another embodiment when X is (CH₂)_(n)NR₄R₁₄ and R₄ and R₁₄ togetherwith the nitrogen cyclize to form an optionally substituted ring, suchas described above, such rings include, but are not limited topyrrolidine, piperidine, piperazine, diazepine, and morpholine. In oneembodiment when X is (CH₂)_(n)NR₄R₁₄, the R₄ and R₁₄ substituentscyclize to form a heterocyclic 5 or 6 membered ring, which ring isoptionally substituted as defined herein. When the R₄ and R₁₄substituents cyclize to form a 4 to 7 membered ring, the optionalsubstitutents are suitably selected from an optionally substitutedalkyl, an optionally substituted aryl, an optionally substitutedheteroaryl, optionally substituted heterocyclic,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇, NR_(4′)R_(14′), or a C₁₋₁₀ alkylsubstituted one or more times by an optionally substituted aryl. Suchsubstitutents more specifically include phenyl, pyrrolidinyl,morpholino, piperazinyl, 4-methyl-1-piperazinyl, piperidinyl,2-oxo-2,3-dihydro-1H-benzimidazol-1-yl,5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, diphenylmethyl, methyl,ethyl, propyl, butyl, amino, methylamino, and dimethylamino.

In one embodiment the X substituent is a 1,4′-bipiperin-1-yl ring whichmay be optionally substituted such as in 4-methyl-1,4′-bipiperin-1-yl;4-piperidinylamino, 4-amino-1-piperidinyl,2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-methyl-1-piperazinyl,(4-morpholinyl)-1-piperidinyl, (4-methyl-1-piperazinyl)-1-piperidinyl,4-ethyl-1-piperazinyl,(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl,5-chloro-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl,4-(1-pyrrolidinyl)-1-piperidinyl, 4-(diphenylmethyl)-1-piperazinyl,4-methylhexahydro-1H-1,4-diazepin-1-yl, 4-propyl-1-piperazinyl, or4-butyl-1-piperazinyl.

In another embodiment, when X is (CH₂)_(n)N(R_(2′))(R_(2″)), and R_(2′)is an optionally substituted C₁₋₁₀ alkyl moiety, and the alkyl issubstituted by (CR₁₀R₂₀)_(n)NR_(e)R_(e′), and R_(e) and R_(e′) arehydrogen, or an optionally substituted C₁₋₁₀ alkyl. Suitably, the Xmoiety is 3-(diethylamino)propylamino,3-(dimethylamino)propyl(methyl)amino,3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino,1-methylethyl)amino-propylamino, (1,1-dimethylethyl)aminopropylamino,(1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino,2-aminoethyl(methyl)amino, or a 2-(dimethylamino)ethyl(methyl)amino.

In another embodiment when X is (CH₂)_(n)N(R_(2′))(R_(2″)), and R₂,moiety is an optionally substituted heteroaryl C₁₋₁₀ alkyl, theheteroaryl moiety is suitably an optionally substituted imidazole.

In one embodiment at least one of R₄ and R₁₄ may be hydrogen when R₄ andR₁₄ are not cyclized. In another embodiment neither R₄ and R₁₄ ishydrogen.

In one embodiment R₃ is a 2,6-difluoro phenyl, R₁ is a phenyl ringsubstituted by and R₁ is selected from C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b),or C(Z)O(CR₁₀R₂₀)_(v)R_(b), or N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b) and alsosubstituted by R_(1′) independently selected at each occurrence fromhydrogen, fluorine, or methyl; g is 1 or 2. Preferably, R₁ issubstituted by C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b) and R_(1′) independentlyselected at each occurrence from hydrogen, fluorine, or methyl. Inanother embodiment, the R_(b) moiety is selected from thiazolyl, C₁₋₁₀alkyl or an optionally substituted aryl. In another embodiment the R_(b)moiety is propyl or 4-fluorophenyl.

In another embodiment, X is suitably selected from(1H-imidazol-2-ylmethyl)amino or 4-methyl-1,4′-bipiperidin-1′-yl,2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-amino-1-piperidinyl,3-(diethylamino)propylamino, 3-(dimethylamino)propyl(methyl)amino,3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino,1-methylethyl)amino-propylamino, (1,1-dimethylethyl)aminopropylamino,(1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino,2-aminoethyl(methyl)amino, or 2-(dimethylamino)ethyl(methyl)amino.

In one embodiment, R₃ is a 2,6-difluoro phenyl, R₁ is phenyl, R_(1′) isindependently selected at each occurrence from hydrogen, fluorine, ormethyl; g is 1 or 2; and the phenyl ring is also substituted in the 3-or 4-position by C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), R_(b) moiety is C₁₋₁₀alkyl or an optionally substituted aryl, preferably propyl or4-fluorophenyl, X is (CH₂)_(n)N(R_(2′))(R_(2″)), and n is 0. In anotherembodiment, X is (CH₂)_(n)N(R_(2′))(R_(2″)), R₂″ is hydrogen, n is 0,and R_(2′) is an alkyl substituted by (CR₁₀R₂₀)_(n)NR_(e)R_(e′). In afurther embodiment, R_(e) and R_(e′) are independently selected from anoptionally substituted C₁₋₄ alkyl, such as methyl, ethyl, isopropyl,n-butyl, or t-butyl, preferably ethyl.

In another embodiment of the present invention, for compounds of Formula(I) the X term may also be the B-Non-Ar-cyc moiety as disclosed in U.S.Pat. No. 6,809,199 whose disclosure is incorporated by reference herein.

As represented by the disclosure in U.S. Pat. No. 6,809,199, Non-Ar—Cycis suitably selected from;

wherein

d is an integer having a value of 1, 2, 3, or 4;

d′ is 0, or an integer having a value of 1, 2, or 3;

d″ is 0, or an integer having a value of 1, 2, or 3;

e is 0, or is an integer having a value of 1, 2, 3, or 4;

e′ is 0, or an integer having a value of 1, 2, or 3;

e″ is 0, or an integer having a value of 1, 2, or 3;

f is 0, or is an integer having a value of 1, 2, or 3;

d+e is 2, 3, 4, 5, or 6;

d′+e″=d

e′+e″=m

Suitably, R_(7′), R₇₇ and R_(77″), are each independently selected fromhydrogen, C₁₋₆ alkyl-group, C₂₋₆ alkenyl-group, C₄₋₆ cycloalkyl-C₀₋₆alkyl-group, N(C₀₋₄ alkyl)(C₀₋₄ alkyl)-C₁₋₄ alkyl-N(C₀₋₄ alkyl)-group,—N(C₀₋₄ alkyl)(C₀₋₄ alkyl) group, C₁₋₃ alkyl-CO—C₀₋₄ alkyl-group, C₀₋₆alkyl-O—C(O)—C₀₋₄ alkyl-group, C₀₋₆alkyl-C(O)—O—C₀₋₄alkyl-group, N(C₀₋₄alkyl)(C₀₋₄ alkyl)-(C₀₋₄ alkyl)C(O)(C₀₋₄ alkyl)-group, phenyl-C₀₋₄alkyl-group, pyridyl-C₀₋₄ alkyl-group, pyrimidinyl-C₀₋₄ alkyl-group,pyrazinyl-C₀₋₄ alkyl-group, thiophenyl-C₀₋₄ alkyl-group, pyrazolyl-C₀₋₄alkyl-group, imidazolyl-C₀₋₄ alkyl-group, triazolyl-C₀₋₄ alkyl-group,azetidinyl-C₀₋₄ alkyl-group, pyrrolidinyl-C₀₋₄ alkyl-group,isoquinolinyl-C₀₋₄alkyl-group, indanyl-C₀₋₄ alkyl-group,benzothiazolyl-C₀₋₄ alkyl-group, any of the groups optionallysubstituted with 1-6 substituents, each substituent independently being—OH, —N(C₀₋₄ alkyl)(C₀₋₄alkyl), C₁₋₄alkyl, C₁₋₆ alkoxyl, C₁₋₆alkyl-CO—C₀₋₄ alkyl-, pyrrolidinyl-C₀₋₄ alkyl-, or halogen; or R₇together with a bond from an absent ring hydrogen is ═O.

Suitably, B is —C₁₋₆alkyl-, —C₀₋₃ alkyl-O—C₀₋₃alkyl-, —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-NH—C₃₋₇cycloalkyl-,—C₀₋₃alkyl-N(C₀₋₃alkyl)-C(O)—C₀₋₃ alkyl-, —C₀₋₃ alkyl-NH—SO₂—C₀₋₃alkyl-, —C₀₋₃ alkyl-, —C₀₋₃alkyl-S—C₀₋₃ alkyl-, —C₀₋₃alkyl-SO₂—C₀₋₃alkyl-, —C₀₋₃alkyl-PH—C₀₋₃ alkyl-, C₀₋₃ alkyl —C(O)—C₀₋₃alkyl, or a direct bond.

Suitably, E₁ is CH, N, or CR₆₆; or B and E₁ together form a double bond,i.e., —CH═C.

Suitably, E₂ is CH₂, CHR₇₇, C(OH)R₇₇ NH, NR₇₇, O, S, —S(O)—, or —S(O)₂—.

Suitably, R₆₆ is independently selected from at each occurrence fromhalogen, C₀₋₄ alkyl, —C(O)—O(C₀₋₄ alkyl), or —C(O)—N(C₀₋₄ alkyl)-(C₀₋₄alkyl).

In an alternative embodiment of this invention, Non-Ary Cyc is:

In another embodiment of the present invention, for compound of Formula(I) herein, the X term may also be the X moiety as disclosed in WO2004/073628, published September 2004, Boehm et al., whose disclosure isincorporated by reference herein.

The term “halo” or “halogens” is used herein to mean the halogens,chloro, fluoro, bromo and iodo.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl or t-butyl andhexyl and the like.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl,1,1-dimethylbut-2-enyl and the like.

As used herein, the term “alkoxy” refers to straight or branched chainalkoxy groups containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy containing atleast 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy and hexyloxy.

As used herein, the term “cycloalkyl” refers to cyclic radicals, such asa non-aromatic hydrocarbon ring containing a specified number of carbonatoms. For example, C₃₋₇cycloalkyl means a non-aromatic ring containingat least three, and at most seven, ring carbon atoms. Representativeexamples of “cycloalkyl” as used herein include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and thelike.

The term “cycloalkenyl” is used herein to mean cyclic radicals, such asa non-aromatic hydrocarbon ring containing a specified number of carbonatoms preferably of 5 to 7 carbons, which have at least one bondincluding but not limited to cyclopentenyl, cyclohexenyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term “aryl” is used herein to mean phenyl, naphthyl, and indene.

The terms “heteroaryl ring”, “heteroaryl moiety”, and “heteroaryl” areused herein to mean a monocyclic five- to seven-membered unsaturatedhydrocarbon ring containing at least one heteroatom selected fromoxygen, nitrogen and sulfur. Examples of heteroaryl rings include, butare not limited to, furyl, pyranyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil. The terms“heteroaryl ring”, “heteroaryl moiety”, and “heteroaryl” shall also usedherein to refer to fused aromatic rings comprising at least oneheteroatom selected from oxygen, nitrogen and sulfur. Each of the fusedrings may contain five or six ring atoms. Examples of fused aromaticrings include, but are not limited to, indolyl, isoindolyl, indazolyl,indolizinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolinyl, purinyl, and phthalazinyl.

The terms “heterocyclic rings”, “heterocyclic moieties”, and“heterocyclyl” is used herein to mean a monocyclic three- toseven-membered saturated or non-aromatic, unsaturated hydrocarbon ringcontaining at least one heteroatom selected from nitrogen, oxygen,sulphur or oxidized sulphur moieties, such as S(O)_(m), and m is 0 or aninteger having a value of 1 or 2. The terms “heterocyclic rings”,“heterocyclic moieties”, and “heterocyclyl” shall also refer to fusedrings, saturated or partially unsaturated, and wherein one of the ringsmay be aromatic, or heteroaromatic. Each of the fused rings may havefrom four to seven ring atoms. Examples of heterocyclyl groups include,but are not limited to, the saturated or partially saturated versions ofthe heteroaryl moieties as defined above, such as tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), azepine, diazepine, aziridinyl,pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl,1,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino andthiomorpholino (including oxidized versions of the sulfur moiety).

The term “arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean a C₁₋₄ alkyl (as defined above) attached to an aryl,heteroaryl or heterocyclic moiety (as also defined above) unlessotherwise indicated.

The term “sulfinyl” is used herein to mean the oxide S(O) of thecorresponding sulfide, the term “thio” refers to the sulfide, and theterm “sulfonyl” refers to the fully oxidized S(O)₂ moiety.

The term “aroyl” is used herein to mean C(O)Ar, wherein Ar is as phenyl,naphthyl, or aryl alkyl derivative such as defined above, such groupinclude but are not limited to benzyl and phenethyl.

The term “alkanoyl” is used herein to mean C(O) C₁₋₁₀ alkyl wherein thealkyl is as defined above.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)_(m) alkyl, suchas methyl thio, methylsulfinyl or methyl sulfonyl; a ketone (—C(O)), oran aldehyde (—C(O)R_(6′)), such as C(O)C₁₀ alkyl or C(O)aryl, whereinR_(6′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl (and wherein the R_(6′) moieties, excluding hydrogen, maythemselves be optionally substituted 1 or 2 times, independently byhalogen; hydroxy; hydroxy substituted alkyl; C₁₋₄ alkoxy; S(O)_(m)C₁₋₄alkyl; amino, mono & di-substituted C₁₋₄ alkyl amino; C₁₋₄ alkyl, orCF₃); C(O)OR_(6′); NR_(4′)R_(14′), wherein R_(4′) and R_(14′) are eachindependently hydrogen or C₁₋₄ alkyl, such as amino or mono or-disubstituted C₁₋₄ alkyl or wherein the R_(4′)R_(14′) can cyclizetogether with the nitrogen to which they are attached to form a 5 to 7membered ring which optionally contains an additional heteroatomselected from O/N/S; C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, or C₃₋₇cycloalkylC₁₋₁₀ alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl,etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀ alkyl, such CF₂CF₂H,or CF₃; an optionally substituted aryl, such as phenyl, or an optionallysubstituted arylalkyl, such as benzyl or phenethyl, wherein these arylcontaining moieties may also be substituted one to two times by halogen;hydroxy; hydroxy substituted alkyl; C₁₋₄ alkoxy; S(O)_(m) C₁₋₄ alkyl;amino, mono & di-substituted C₁₋₄ alkyl amino; C₁₋₄ alkyl, or CF₃.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical use. Salts and solvates ofcompounds of the invention which are suitable for use in medicine arethose wherein the counterion or associated solvent is pharmaceuticallyacceptable. However, salts and solvates having non-pharmaceuticallyacceptable counterions or associated solvents are within the scope ofthe present invention, for example, for use as intermediates in thepreparation of other compounds of the invention and theirpharmaceutically acceptable salts and solvates.

As used herein, the term “pharmaceutically acceptable derivative”, meansany pharmaceutically acceptable salt, solvate or prodrug e.g. ester, ofa compound of the invention, which upon administration to the recipientis capable of providing (directly or indirectly) a compound of theinvention, or an active metabolite or residue thereof. Such derivativesare recognizable to those skilled in the art, without undueexperimentation. Nevertheless, reference is made to the teaching ofBurger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent of teaching such derivatives. In one embodiment of thepresent invention the pharmaceutically acceptable derivatives are salts,solvates, esters, carbamates and phosphate esters. In another embodimentpharmaceutically acceptable derivatives are salts, solvates and esters.In yet another embodiment, pharmaceutically acceptable derivatives aresalts and esters, in particular salts.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid.

The compounds of the present invention may be in the form of and/or maybe administered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The salt may precipitatefrom solution and be collected by filtration or may be recovered byevaporation of the solvent.

Pharmaceutically acceptable salts of compounds of Formula (I) maysuitably be formed with a pharmaceutically acceptable cation, forinstance, if a substituent group comprises a carboxy moiety. Suitablepharmaceutically acceptable cations are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium and quaternaryammonium cations.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. As used herein, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (inthis invention, a compound of formula (I) or a salt thereof) and asolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid.Preferably the solvent used is a pharmaceutically acceptable solvent.Examples of suitable pharmaceutically acceptable solvents include water,ethanol and acetic acid. Most preferably the solvent used is water. Acomplex with water is known as a “hydrate”. Solvates of the compound ofthe invention are within the scope of the invention.

Compounds of Formula (II) are represented by the structure:

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;-   Rg is a C₁₋₁₀ alkyl;-   m is 0, or an integer having a value of 1, or 2;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted.

The optional substituents for the R₃ moiety are as defined herein forcompounds of Formula (I).

In one embodiment of the invention, Rx is chloro. In another embodiment,Rg is methyl. In a further embodiment, m is 0. In another embodiment mis 1, and R₃ is an optionally substituted phenyl (as defined in Formula(I)).

In another embodiment, m is 0, Rg is methyl, Rx is chloro and R₃ is anoptionally substituted phenyl (as defined in Formula (I)).

Compounds of Formula (III) are represented by the structure:

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃:-   X is R₂, OR_(2″) S(O)_(m)R_(2″) (CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′),    (CH₂)_(n′)N(R₁₁)C(O)R_(2′), (CH₂)_(n)NR₄R₁₄, or    (CH₂)_(n′)N(R_(2′))(R_(2′)), or N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—O—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀ alkyl, aryl, arylC₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀-alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or R₂ is the moiety    (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃);

R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,aryl, arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic,or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties,excluding hydrogen, may be optionally substituted;

-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀-alkyl, heteroaryl,    heteroarylC₁₋₁₀-alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, and wherein these moieties, excluding hydrogen, may be    optionally substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, aryl C₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted;-   R₄ and R₁₄ are each independently selected from hydrogen, C₁₋₁₀    alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₁₄    alkyl, heterocyclic, heterocylic C₁₋₄ alkyl, heteroaryl or a    heteroaryl C₁₋₄ alkyl moiety, and wherein each of these moieties,    excluding hydrogen, may be optionally substituted; or the R₄ and R₁₄    together with the nitrogen which they are attached form an    optionally substituted heterocyclic ring of 4 to 7 members, which    ring optionally contains an additional heteroatom selected from    oxygen, sulfur or nitrogen;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;-   R_(10′) is independently selected at each occurrence from hydrogen    or C₁₋₄alkyl;-   R₁₁ is independently selected from hydrogen or C₁₋₄alkyl;-   n′ is independently selected at each occurrence from 0 or an integer    having a value of 1 to 10;-   m is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6; or-   t is an integer having a value of 2 to 6.

Suitably, Rx is chloro, bromo, iodo, or O—S(O)₂CF₃. In an embodiment ofthe invention, Rx is chloro.

The X term moieties and their substituent groups, etc. are as definedherein for compounds of Formula (I).

Compounds of Formula (IV) are represented by the structure:

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   R₁ is R₁ is an aryl, aryl C₂₋₁₀ alkyl, heteroaryl, heteroaryl C₂₋₁₀    alkyl; aryl C₂₋₁₀ alkenyl, arylC₂₋₁₀ alkynyl, heteroaryl C₂₋₁₀    alkenyl, heteroaryl C₂₋₁₀ alkynyl, C₂₋₁₀alkenyl, or C₂₋₁₀ alkynyl    moiety, which moieties may be optionally substituted;-   Rg is an optionally substituted C₁₀ alkyl;-   m is 0 or an integer having the value of 1 or 2;-   R₃ is a C₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₀ alkyl, aryl,    arylC₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic or a    heterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties    may be optionally substituted.

Suitably R₁ and R₃ are substituted as defined herein for compounds ofFormula (I). In one embodiment, R₁ is an optionally substituted aryl orheteroaryl ring, preferably and optionally substituted aryl.

In another embodiment Rg is methyl. In a further embodiment, m is 0 or2.

Compounds of Formula (V) are represented by the formula:

wherein

-   Ry is chloro, bromo, iodo, O—S(O)₂CF₃; and-   Rg is a C₁₋₁₀ alkyl.

In one embodiment of the invention, Ry is bromo, iodo, or O—S(O)₂CF₃.

In another embodiment of the invention, Rg is methyl.

The general preparation of analogs around thepyrido[2,3-d]pyrimidin-7-one template is shown in the Schemes, Schemes 1to 4 below. While a particular formula with particular substituentgroups is shown herein, e.g. Rg as methyl, or Rx or LG2 as chloro, thesynthesis is applicable to all formulas and all substituent groups asdescribed herein.

The synthesis described herein, Schemes 1 to 4, start with a 4,6-Rysubstituted-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (1), such asdescribed in Formula (V). Treatment of 1, Scheme 1, with an optionallysubstituted aniline in the presence of an olefin forming agent, such asbis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)-phosphonate or anacylating agent, such as acetic acid anhydride affords thepyrido[2,3-d]pyrimidin-7-one, 2. Oxidation of 2 with a peracid, such as3-chloroperoxybenzoic acid (m-CPBA) yields compound 3. This is followedby substitution of 3 in C2 position with a suitable X moiety asdescribed in Formula (I) herein. In this scheme, substitution of the C2position is demonstrated with serinol to furnish compound 4. Palladium(0) mediated Suzuki cross-coupling affords compound 5. Other crosscoupling reactions known in the art may also be suitable for use herein.

In Routes 1 & 3; Schemes 1 & 3, Compound 1 to Compound 2, while theolefin forming reagentBis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate is used,alternative cyclization reagents, include, but are not limited toBis(2,2,2-trifluoroethyl)-(ethoxycarbonylmethyl)phosphonate,Bis(2,2,2-trifluoroethyl)-(isopropoxycarbonylmethyl)phosphonate,(Diethoxy-phosphoryl)-acetic acid methyl ester,(Diisopropoxy-phosphoryl)-acetic acid methyl ester,(Diphenyloxy-phosphoryl)-acetic acid methyl ester,(Diethoxy-phosphoryl)-acetic acid ethyl ester,(Diisopropoxy-phosphoryl)-acetic acid ethyl ester, or(Diphenyloxy-phosphoryl)-acetic acid ethyl ester.

While this reaction as shown in Scheme 1 and Scheme 3 uses triethylamineas a base, suitable alternative bases can include, but are not limitedto pyridine, diisopropyl ethyl amine, or pyrrolidone, or combinationsthereof.

Further, while the reaction scheme as shown in Scheme 1 and Scheme 3utilizes tetrahydrofuran as a solvent, it is recognized that suitablealternative organic solvents can be used. Such solvents include, but arenot limited to chloroform, methylene chloride, acetonitrile, toluene,DMF, or n-methylpyrrolidine, or combinations thereof.

The reaction temperature of this particular step in the reaction schemecan be varied from room temperature to >100° C., i.e. reflux temperatureof the solvent. Alternatively, this reaction process step may beperformed under suitable microwave conditions.

In Routes 2 & 4, Schemes 2 & 4, Compound 1 to Compound 2, while thereagent acetic anhydride is shown, this reagent can be replaced withacetyl chloride, or any other suitably acylating reagent.

Further, while the reaction scheme as shown in Scheme 2 and Scheme 4utilizes chloroform as a solvent, it is recognized that suitablealternative organic solvents can be used. Such solvents include, but arenot limited to tetrahydrofuran, methylene chloride, acetonitrile,toluene, DMF, n-methylpyrrolidine, or dioxane, or combinations thereof.

The reaction temperature of this particular step in the reaction schemecan be varied from room temperature to >100° C., i.e. reflux temperatureof the solvent. Alternatively, this reaction process step may beperformed under suitable microwave conditions.

In Routes 1 & 2; Schemes 1 & 2, Compound 2 to Compound 3, or for Routes3 & 4, Schemes 3 & 4, Compound 6 to Compound 7, while the oxidizingreagent 3-chloroperoxybenzoic acid (m-cPBA) is used, alternativereagents, include but are not limited to hydrogen peroxide, sodiumperiodinate, potassium periodinate, Oxone, OsO4, catalytic tertiaryamine N-oxide, peracids, such as aryl peracids, i.e. perbenzoic and theaforementioned m-cPBA, or alkylperacids, as such peracetic acid andpertrifluoroacetic acid, oxygen, ozone, organic peroxides, peroxide(H₂O₂), and inorganic peroxides, potassium and zinc permanganate,potassium persulfate. It is recognized that the peroxide agents can beused in combination with sodium tungstate, acetic acid or sodiumhyperchlorite.

It is recognized that the oxidation process may in fact yield Compound3, or Compound 7, but may also result in the corresponding sulfone, aswell as the sulfoxide, or mixtures thereof.

This reaction step, while demonstrated in the schematics with methylenechloride as the solvent, may use alternative organic solvents other thanprimary amines or alcohols which include, but are not limited tochloroform, acetone, DMF, THF, acetonitrile, dioxane, or DMSO, orcombinations thereof. This reaction step may be conducted at about 0° C.to room temperature.

In Routes 1 & 2; Schemes 1 & 2, Compound 3 to Compound 4, or for Route 3& 4, Schemes 3 & 4, Compound 7 to Compound 5, the reaction solvent ofDMF may alternatively be replaced with other suitable anhydrous organicsolvents, which does not contain a nucleophile, which include but arenot limited to THF, methylene chloride, acetone, acetonitrile, toluene,chloroform, n-methyl-pyrrolidine, or dioxane, or combinations thereof.

This temperature step may be conducted at room temperature to >100° C.,i.e. reflux temperature of the solvent. Alternatively, this reactionprocess step may be performed under suitable microwave conditions.

In Routes 1 & 2, Schemes 1 & 2, Compound 4 to Compound 5, or for Routes3-4, Schemes 3-4, Compound 2 to Compound 6 wherein Compound 2 or 4 arecoupled to arylboronic acids, heteroarylboronic acids or thecorresponding boronic acid esters under standard Suzuki couplingconditions. These reaction conditions utilize a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium (0), which has been shown toprovide good yields of either compound 5 or 6. The reaction conditionsmay be from room temperature to about 250° C., by heating in an oilbath, or with microwave irradiation. If desired, these Suzuki couplingreactions may be run under microwave conditions.

The aryl or heteroaryl boronic acid or ester intermediates can besynthesized either by the palladium catalyzed coupling of an aryl halideand 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane or thetransmetalation of an aryl halide with a Grignard reagent, e.g.,isopropylmagnesium bromide followed by a trialkylborate (e.g.,triethylborate) in a suitable solvent like THF.

Alternatively, the coupling reaction of 2 or 4 may be performedutilizing aryl or heteroaryl organozinc, organocopper, organotin, orother organometallic reagents known to afford cross-coupling productssuch as 5 or 6 [See for example: Solberg, J.; Undheim, K. Acta ChemicaScandinavia 1989, 62-68, whose disclosure is incorporated by referenceherein].

Using the reaction procedures described in the aforementioned WO02/059083, it has been found that compounds of Formula (III) asdescribed herein, were unable to be synthesized following thoseprocedures. The present invention provides for an alternative method tosynthesize compounds of Formula (I) having differing R₁ substituents onthe C4 position of the pyrido[2,3-d]pyrimidin-7-one pharmacophore. Thesesubstituents may be introduced to this position after thepyrido[2,3-d]pyrimide-7-one pharmacophore is substituted with functionalgroups at the C₂ and N₈ position. This particular substitution has notpreviously been available using the reaction conditions as set forth inWO 02/059083.

While it is possible to produce individual compounds using the processillustrated herein, a benefit for these reaction pathways lies in itsability to optimize leads and to make arrays for combinatorialchemistry, with various R₁, R₂, and R₃ substituents.

Another aspect of the invention is a process to make compounds ofFormula (I) as defined herein, which comprises reacting a compound ofFormula (III), as defined herein with a coupling agent selected from anarylboronic acid, or a heteroarylboronic acid or their correspondingboronic acid esters, with a suitable palladium catalyst to yield acompound of Formula (I). This coupling process takes place understandard Suzuki conditions.

Suitably the arylboronic acids, heteroarylboronic acids, or theircorresponding boronic acid esters are R₁-boronic acid or an R₁-boronicacid ester; e.g. R₁B(OH)₂, R₁B(O—C₁₋₄ alkyl)₂, or

wherein R₁, R₁₀, and R₂₀ is as defined for compounds of Formula (I)herein; and r is an integer having a value of 2 to 6.

The coupling conditions include the use of appropriate solvents. Thesesolvents include, but are not limited to dioxane, THF, DMF, DMSO, NMP,acetone, water, or a combination or a mixture thereof. Preferably, thesolvent is THF/H₂O, or dioxane/H₂O.

The coupling conditions also include the presence of catalytic amount ofcatalysts and these catalysts include, but not limited totetrakis(triphenylphosphine)-palladium (0), PdCl2, Pd(OAc)2,(CH3CN)2PdCl2, Pd(dppf)2, or[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II).

The coupling reaction may or may not require the presence of a base.Suitable bases include, but are not limited to NaHCO₃, KHCO₃, Na₂CO₃,K₂CO₃, KOAc or combination or mixture thereof. Preferably, the base isK₂CO₃ and KOAc.

The coupling reaction may or may not require heating. The heating can becarried out with a regular oil bath or microwave irrediations and thetemperature can be varied from room temperature to >100° C., i.e. refluxtemperature of the solvent. The coupling reaction may or may not requirea sealed reaction vessal and the internal pressure can be varied fromone atmosphere to 100 atmospheres.

The aryl or heteroaryl boronic acid or ester intermediates containingthe R₁ moiety, used in the Suzuki coupling reactions may or may not becommercially available and they can be prepared by utilizing propermethods in the literature known to those with appropriate training.Examples of these methods include, but not limited to palladiumcatalyzed coupling of an aryl halide and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane or thetransmetalation of an aryl halide with a Grignard reagent, e.g.,isopropylmagnesium bromide followed by a trialkylborate (e.g.,triethylborate) in a suitable solvent. These solvents include, but notlimited to CH₂Cl₂, chloroform, CH₃CN, benzene, THF, hexane, ethyl ether,tert-butyl methyl ether, DMSO, DMF, toluene, n-methyl-pyrrolidine,dioxane. The reaction temperature can be varied from −78° C. to >100°C., i.e. reflux temperature of the solvent. Alternatively, this reactionprocess step may or may not be performed under suitable microwaveirradiation conditions. This reaction may or may not require a sealedreaction vessal and the internal pressure can be varied from oneatmosphere to 100 atmospheres.

One embodiment of the invention are the arylboronic acids and esterswhich are generically referred to as R₁B(OH)₂, R₁B(O—C₁₋₄ alkyl)₂, or

wherein

R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄ alkyl;

r is an integer having a value of 2 to 6;

R₁ is an optionally substituted phenyl, as defined according to Formula(I).

Suitably, the phenyl ring is substituted by one or more timesindependently at each occurrence by halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v′) NR_(d)R_(d′),(CR₁₀R₂₀)_(v′) C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_(v′)OR₁₃,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)COR_(a′),(CR₁₀R₂₀)_(v)C(O)H, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁₁,N(R_(10′))C(Z)R₁₁, N(R_(10′))S(O)₂R₇, C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b),C(Z)O(CR₁₀R₂₀)_(v)R_(b), N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); orN(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b); and wherein

-   R_(a′) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,    C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄    alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,    heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,    (CR₁₀R₂₀)v N(R_(10′))S(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein    the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally    substituted;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   R_(d) and R_(d′) are each independently selected from hydrogen, C₁₋₄    alkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylC₁₋₄alkyl, or the R_(d) and    R_(d′) together with the nitrogen which they are attached form an    optionally substituted heterocyclic ring of 5 to 6 members, which    ring optionally contains an additional heteroatom selected from    oxygen, sulfur or NR_(9′), and wherein the R_(d) and R_(d′) moieties    which are C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄ alkyl, and    the R₄ and R₁₄ cyclized ring are optionally substituted;-   R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆    alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and wherein each of these    moieties may be optionally substituted;-   R₈ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein these moieties, excluding hydrogen, may be    optionally substituted independently at each occurrence;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   m is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   v is independently selected at each occurrence from 0, or an integer    having a value of 1 to 2.-   v′ is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or heteroaryl C₁₋₄ alkyl; or the R₄ and R₁₄ together with    the nitrogen which they are attached form an unsubstituted or    substituted heterocyclic ring of 4 to 7 members, which ring    optionally contains an additional heteroatom selected from oxygen,    sulfur or nitrogen; and wherein all of these moieties, excluding    hydrogen, are optionally substituted;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′) can    cyclize together with the nitrogen to which they are attached to    form an optionally substituted 5 to 7 membered ring which optionally    contains an additional heteroatom selected from oxygen, sulfur or    NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₄₁R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′), S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄ alkyl;-   R_(10′) is independently selected at each occurrence from hydrogen    or C₁₋₄ alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen, or    C₁₋₄ alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; and-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted.

In one embodiment, the phenyl ring is substituted byC(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), or N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b),and optionally another substituent (R_(1′))g, and g is 1 or 2. R_(b) issuitably as defined in Formula (I) herein. Suitably, R_(1′) isindependently selected at each occurrence from halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v′) NR_(d)R_(d′),(CR₁₀R₂₀)_(v)C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_(v′)OR₁₃.Preferably R_(1′) is independently selected at each occurrence from C₁₋₄alkyl, such as methyl, or halogen, such as fluorine or chlorine orbromine, or halo-substituted-C₁₋₄ alkyl, such as CF₃.

In one embodiment, the C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), is substitutedon the phenyl ring in the 4-position or the 5-position, preferably the5-position. If an R_(1′) moiety is present, it is preferably in the2-position, and R_(1′) is independently selected at each occurrence fromC₁₋₄ alkyl, such as methyl, or halogen, such as fluorine or chlorine orbromine. Preferably the aryl is 4-methyl-N-1,3-thiazol-2-ylbenzamide,N-(4-fluorophenyl)-4-methylbenzamide, or 4-methyl-N-propylbenzamide.

In another embodiment the phenyl ring is substituted one or more times,preferably 1 to 4 times by R_(1′) and R_(1′) is independently selectedat each occurrence from halogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄alkyl, cyano, nitro, (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂,SR₅, S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_(v′)OR₁₃. Preferably, the phenyl ringis di-substituted in the 2,4-position. In another embodiment R_(1′) isindependently selected at each occurrence from C₁₋₄ alkyl, such asmethyl, or halogen, such as fluorine or chlorine or bromine, orhalo-substituted-C₁₋₄ alkyl, such as CF₃. Preferably, the aryl isphenyl, 2-methyl-4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl,2-fluorophenyl, or 2-methyl-3-fluorophenyl.

Another aspect of the invention is another process to make compounds ofFormula (I) as defined herein, which comprises reacting a compound ofFormula (III), as defined herein utilizing aryl or heteroarylorganozinc, organocopper, organotin, or other organometallic reagentsknown in the art to afford a cross-coupling product of the desired R1moiety in the C4 position of the template yielding a compound of Formula(I).

This coupling reaction may be performed utilizing aryl or heteroarylorganozinc (e.g., R₁—ZnBr, R₁—ZnCl, R₁—Zn—R₁), organocopper [e.g.,(R₁)₂—CuLi], organotin (e.g., R₁—Sn(CH₃)₃, R₁—Sn(CH₂CH₂CH₂CH₃)₃], orother organometallic reagents to afford the cross-coupling product. TheR₁ aryl and heteroaryl moiety is as defined for Formula (I) herein. Ifthe desired aryl or hetero aryl organozinc (e.g., R₁—ZnBr, R₁—ZnCl,R₁—Zn—R₁), organocopper [e.g., (R₁)₂—CuLi], organotin (e.g.,R₁—Sn(CH₃)₃, R₁—Sn(CH₂CH₂CH₂CH₃)₃], or other organometallic reagent isnot commercially available, they can readily be prepared by utilizingproper methods, known in the literature.

These types of coupling reactions require the use of appropriatesolvents. Such solvents include, but are not limited to dioxane, THF,methylene chloride, chloroform, benzene, hexane, ethyl ether, tert-butylmethyl ether or a combination or a mixture thereof.

The coupling reaction may, or may not, require the presence of catalyticamount of a catalyst. Such catalysts include, but are not limited totetrakis(triphenylphosphine)palladium (0), PdCl₂, Pd(OAc)₂,(CH₃CN)₂PdCl₂, Pd(dppf)₂.

The reaction temperature can be varied from −78° C. to >100° C., i.e.reflux temperature of the solvent. Alternatively, this reaction processstep may be performed under suitable microwave irradiation conditions,if needed. This reaction may, or may not, require a sealed reactionvessel and the internal pressure can be varied from one atmosphere to100 atmospheres.

Suitably, the R₁ moiety is as defined for compounds of Formula (I)herein.

In one embodiment, the R₁ moiety is an optionally substituted aryl ring,preferably a phenyl ring. In another embodiment, the phenyl ring issubstituted by C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), orN(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b), and optionally another substituent(R_(1′))g, and g is 1 or 2. R_(b) is suitably as defined in Formula (I)herein. Suitably, R_(1′) is independently selected at each occurrencefrom halogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,(CR₁₀R₂₀)_(v′) NR_(d)R_(d′), (CR₁₀R₂₀)_(v′) C(O)R₁₂, SR₅, S(O)R₅,S(O)₂R₅, or (CR₁₀R₂₀)_(v′) OR₁₃. Preferably R_(1′) is independentlyselected at each occurrence from C₁₋₄ alkyl, such as methyl, or halogen,such as fluorine or chlorine or bromine, or halo-substituted-C₁₋₄ alkyl,such as CF₃.

In one embodiment, the C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), is substitutedon the phenyl ring in the 4-position or the 5-position, preferably the5-position. If an R_(1′) moiety is present, it is preferably in the2-position, and R_(1′) is independently selected at each occurrence fromC₁₋₄ alkyl, such as methyl, or halogen, such as fluorine or chlorine orbromine. Preferably the aryl is 4-methyl-N-1,3-thiazol-2-ylbenzamide,N-(4-fluorophenyl)-4-methylbenzamide, or 4-methyl-N-propylbenzamide.

In another embodiment the phenyl ring is substituted one or more times,preferably 1 to 4 times by R₁, and R_(1′) is independently selected ateach occurrence from halogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl,cyano, nitro, (CR₁₀R₂₀)_(v′) NR_(d)R_(d′), (CR₁₀R₂₀)_(v′) C(O)R₁₂, SR₅,S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_(v′) OR₁₃. Preferably, the phenyl ring isdi-substituted in the 2,4-position. In another embodiment R_(1′) isindependently selected at each occurrence from C₁₋₄ alkyl, such asmethyl, or halogen, such as fluorine or chlorine or bromine, orhalo-substituted-C₁₋₄ alkyl, such as CF₃. Preferably, the aryl moiety isa 2-methyl-4-fluorophenyl.

Additional methods to produce compounds of Formula (II), wherein G1 isNH, are shown in Scheme 5 below.

Method A is for conversion of 1 to 2. Examples of the methods include,but are not limited to condensation with NH₂OH followed by treatmentwith thionyl chloride (SOCl₂) [e.g., Santilli et al., J. Heterocycl.Chem. (1971), 445-53] or oxidation of —CHO group to —COOH followed byformation of a primary amide (—CONH₂) and treatment with POCl₃. SuitableMethod A can also be utilized to furnish the conversion of 4 to 3-Scheme5.

Leaving groups (LG, described as Leaving group 1 (LG1) & LG2) in 1 (or2), or elsewhere, can be independently selected from —Cl, —Br, —I, or—OTf and these groups can be installed through the transformation ofanother functional group (e.g. —OH) by following the methods well knownin the art (e.g., treatment of the —OH compound with POCl₃).

Method B is for selective displacement of suitable aldehyde 1 or nitrile2 with an amine (R₃—NH₂). This type of displacement may be achievedusing triethylamine and the desired amine R₃NH₂ in chloroform at roomtemperature for 10 minutes. The reaction was very effective for a rangeof alkyl amines (78-95% yield). For aryl or heteroaryl amines, elevatedtemperatures (reflux), longer reaction time (24 hours) and presence ofNaH (or Na) may be necessary for reaction completion. Use of the basecould be omitted when 3 or more equivalent of the desired amine wereused. Other suitable bases include but are not limited to pyridine,diisopropyl ethylamine or pyrrolidine, which may also be used in anappropriate organic solvent, including but not limited to THF, diethylether, DCM, DMF, DMSO, toluene or dioxane.

Method C is for the reduction of nitrile 3 to amine 5. 5 may beconsidered a primary amine (NH₂), a secondary amine (because of —NH(R3))or an amine (as it contains basic nitrogen). This method includes, butis not limited to BH₃ in appropriate organic solvent, such as THF, DCM,toluene, DMSO, diethyl ether or dioxane. Other suitable reductionreagents, include but are not limited to NaBH₄, LAH or DIBAL. Method Cmay require elevated temperatures (e.g., heating, refluxing orirradiating with microwave). Another example of the method ishydrogenation (H₂) in the presence of transition metals (e.g., Pd/C,Raney-Ni, PdCl₂).

Method D is for the cyclization of 5 to 6. This method requires thepresence of a cyclization reagent (e.g., CDI, COCl₂, tri-phosgene, orphenyl chloroformate methyl chloroformate). Presence of a suitable basemay help the reaction to go to completion and examples of the baseinclude, but not limited to triethyl amine, diisopropylethylamine orpyrrolidine. Reaction solvent can be DCM, THF, toluene, DMSO, or DMF.

Compounds of Formula (VI) are represented by the formula:

wherein

-   LG2 is chloro, bromo, iodo, or O—S(O)₂CF₃;-   LG1 is chloro, bromo, iodo, or O—S(O)₂CF₃; and-   Rg is an optionally substituted C₁₋₁₀ alkyl.

In one embodiment, LG2 is chloro. IN a further embodiment, LG1 ischloro. In another embodiment, Rg is methyl.

Compounds of Formula (VII) are represented by the formula:

wherein

-   LG2 is chloro, bromo, iodo, O—S(O)₂CF₃;-   Rg is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted.

Suitably R₃ is substituted as defined herein for compounds of Formula(I).

In one embodiment, Rg is methyl. In another embodiment, LG2 is chloro.

Another aspect of the invention are compounds of Formula (VIII)represented by the formula:

wherein

-   LG2 is chloro, bromo, iodo, O—S(O)₂CF₃;-   Rg is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted.

Suitably R₃ is substituted as defined herein for compounds of Formula(I).

In an embodiment of the invention LG2 is chloro. In another embodiment,Rg is methyl. In another embodiment, LG2 is chloro, Rg is methyl, and R₃is an optionally substituted phenyl.

Another aspect of the present invention is the novel process, shown inScheme-6 below, to make the transformation of a compound of Formula(VIII) to a compound of Formula (II) wherein Rx is now defined as LG2,and m=0.

Method J is for imine formation to convert compound 13 to a compound ofFormula (II) wherein m is 0, compound 14. This can be achieved byfollowing various strategies known in the art. Strategies include, butare not limited to treatment with an acid including TFA, HOAc, HCl,H₂SO₄ or a Lewis acid (e.g., AlCl₃). This conversion may requireelevated temperatures (e.g., heat, solvent reflux, microwaveirradiation) in appropriate organic solvents (e.g., THF, CH₂Cl₂,toluene, DMSO, CH₃CN or dioxane).

Compounds of Formula (VIII) (compound 13-Scheme 7) may be made byreacting the compound 4 using Method I as described below. Compound 4may be obtained from compound 1 using Method B as described above.

Method I is for urea formation to convert 4 to 13. This can be achievedby following strategies well-established in the art. Strategies include,but are not limited to reaction with suitably substituted isocyanate,such as ClSO₂NCO (or Me₃SiNCO) in a aprotic organic solvent, such astoluene, methylene chloride, chloroform, benzene, THF, hexane,optionally with a non-nucleophilic base, such as triethylamine,diisopropyl ethylamine, pyridine, followed by reaction with ammonia orH₂O; or by reaction with COCl₂ (CDI, or triphosgene) ormethylchloroformate or other chloroformates in an aprotic organicsolvent, such as toluene, methylene chloride, chloroform, benzene, THF,hexane, optionally with a non-nucleophilic base, such as triethylamine,diisopropyl ethylamine, pyridine, followed by treatment with NH₃ (orNH₄OH); or by reaction with ClCO₂Me (or ClCO₂Et) in a aprotic organicsolvent, such as toluene, methylene chloride, chloroform, benzene, THF,hexane, optionally with a non-nucleophilic base, such as triethylamine,diisopropyl ethylamine, pyridine followed by treatment with NH₃ (orNH₄OH) or reaction with NH₂CO₂(t-Bu), followed by reaction with ammonia.This reaction may, or may not, require heating (e.g, temperature betweenr.t. and 250° C.). The heating can be carried out in any manner and mayinclude the use of an oil bath or microwave irradiation.

Another aspect of the invention is a process for making a compound ofFormula (III):

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;    and wherein X and R₃ are as defined above for compounds of Formula    (I); comprising reacting a compound of the formula

wherein

-   G1 is CH₂ or NH:-   G2 is carbon or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;-   Rg is a C₁₋₁₀ alkyl;-   m is an integer having a value of 1, or 2;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted;-   with X—Y wherein X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′), (CH₂)_(n′)N(R₁₁)C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, or (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′; and R₂, R_(2′), m, n′, R₁₁,    R_(10′), R_(h) and R_(q)R_(q′) are as defined according to Formula    (I or JJJ) herein; and

Y is hydrogen, a metal, a boronic acid derivative, or a trialkyl tinderivative, in an anhydrous organic solvent which does not contain anucleophile to yield a compound of Formula (III).

In the transformation of (II) to (III), when Y is hydrogen then X is thefollowing:

-   a) X=OR_(2″) or X is S(O)_(m)R_(2′) (and m=0); or-   b) X is (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2″)    (CH₂)_(n′)N(R_(10′))C(O)R_(2″) (CH₂)_(n′)NR₄R₁₄, or    (CH₂)_(n′)N(R_(2′))(R_(2″)) and n′=0; or-   c) X=R₂ and R₂=(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), q′=0, and    X₁ is N(R_(10′)), O, S(O)_(m) and m=0.-   d) when X is N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′.

In the transformation of (II) to (III), when Y is a metal, such as Li,Mg, or any other appropriate metal or metal complex; then X is thefollowing:

-   a) X is R₂, and R₂ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl    C₁₋₁₀ alkyl, aryl, arylC₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀    alkyl, heterocyclic, or a heterocyclyl C₁₋₁₀ alkyl moiety.

In the transformation of (II) to (III), when Y is a boronic acid,(B(OH)₂) or boronic ester derivatives; then X is the following

-   a) X=R₂, and R₂=aryl, or heteroaryl.

When Y is a trialkyl tin derivative, such as (C₁₋₄ alkyl)₃Sn, then

-   a) X=R₂, and R₂=aryl, or heteroaryl.

It is recognized that for compounds of Formula (II) or (III) when G1 isNH, the nitrogen may need to be protected under standard conditions, andthen deprotected after the transformation, as desired.

The anhydrous organic solvents include, but are not limited to CH₂Cl₂,chloroform, CH₃CN, benzene, THF, hexane, ethyl ether, tert-butyl methylether, DMSO, DMF and toluene.

This reaction may or may not require heating (e.g., temperature betweenr.t. and 300° C.) and the heating can be carried out with, but notlimited to a regular oil bath or microwave irradiations;

This reaction may or may not require the presence of bases, and thebases include, but are not limited to triethyl amine, diisopropyl ethylamine, NaH, n-Buli, tert-BuLi, tert-BuOK, Li₂CO₃, Cs₂CO₃ and pyridine.It is recognized that some of these bases will be incompatible with theorganic solvents specified above.

This reaction may or may not be carried out in a sealed reaction vesseland the internal pressure may be higher than one atmosphere (e.g.,between 1 and 100 atmospheres).

This reaction may or may not require the presence of catalytic amount ofcatalysts containing transition metals (e.g., Pd, Cu, Ni or W). Thesecatalysts include but are not limited to Pd/C, Pd(PPh₃)₄ and PdCl₂.

Another aspect of the invention is a process for making a compound ofFormula (III),

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;    and wherein X and R₃ are as defined above for compounds of Formula    (III);    comprising reacting a compound of the formula

wherein

-   G1 is CH₂ or NH:-   G2 is CH or nitrogen;-   Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;-   Rg is a C₁₋₁₀ alkyl;-   m is an integer having a value of 1, or 2;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted;-   with X—Y wherein X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′), (CH₂)_(n′)N(R₁₁)C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, or (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′; and R₂, R_(2′), m, n′, R₁₁,    R_(10′), R_(h) and RqRq′ are as defined according to Formula (I    or III) herein; and    and Y is NH₂, NH(R₁₀), OH, or SH, in an anhydrous organic solvent to    yield a compound of Formula (III), provided that    -   a) X is R₂ and R₂ is hydrogen, C₁— loalkyl, C₃₋₇ cycloalkyl,        C₃₋₇ cycloalkylalkyl, aryl, arylC₁₋₁₀-alkyl, heteroaryl,        heteroarylC₁₋₁₀-alkyl, heterocyclic, or a        heterocyclylC₁₋₁₀-alkyl; or    -   b) X is (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′),        (CH₂)_(n′)N(R_(10′))C(O)R_(2′), (CH₂)_(n′)N4R₁₄,        (CH₂)_(n′)N(R_(2′))(R_(2″)), and n′ is greater than 2.

The anhydrous organic solvents include, but are not limited to CH₂Cl₂,chloroform, CH₃CN, benzene, THF, hexane, ethyl ether, tert-butyl methylether, DMSO, DMF and toluene, DMF, acetone, toluene,n-methyl-pyrrolidine, or dioxane, or a combination or mixture thereof.

This reaction may or may not require heating (e.g., temperature betweenroom temperature and 300° C.) and the heating can be carried out with,but not limited to a regular oil bath or microwave irradiations;

This reaction may or may not require the presence of bases, and thebases include, but are not limited to triethyl amine, diisopropyl ethylamine, NaH, n-Buli, tert-BuLi, tert-BuOK, Li₂CO₃, Cs₂CO₃ and pyridine.It is recognized that some of these bases will be incompatible with theorganic solvents specified above.

This reaction may or may not be carried out in a sealed reaction vesseland the internal pressure may be higher than one atmosphere (e.g.,between 1 and 100 atmospheres).

This reaction may or may not require the presence of catalytic amount ofcatalysts containing transition metals (e.g., Pd, Cu, Ni or W). Thesecatalysts include but are not limited to Pd/C, Pd(PPh₃)₄ and PdCl₂. Itis recognized that use of these metals is generally not needed forsimple transformations.

Exemplified Compounds of Formulas (II)

-   4-Chloro-8-(4-trifluoromethyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776438)-   4-Chloro-8-(4-trifluoromethyl-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776441)-   4-Chloro-8-(2,4-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776439)-   4-Chloro-8-(2,4-difluoro-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776442)-   4-Chloro-8-(2,6-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776440)-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;    and (SB-776446)-   4-Chloro-8-(2,6-difluoro-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one.    (SB-776443)

Exemplified Compounds of Formula (III)

-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776444)-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;    (SB-776445)

Exemplified compounds of Formula (I) which may be produced using theprocesses described herein include:

-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(2-methylsulfanyl-phenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-739796-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(3-methylsulfanyl-phenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB 739804-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-phenyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB741658-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(3-chlorophenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-741922-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(4-chlorophenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-741923-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(3,4-diflorophenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-742172-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(2-chlorophenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-742364-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(4-methoxyphenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-742501-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(3-methoxyphenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-742502-   2-(Hydroxy-hydroxymethyl-ethylamino)-4-(2-methoxyphenyl)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-742503-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-methylsulfanyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-743869-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-methylsulfanyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746098-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-methylsulfanyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746099-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746100-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-methoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746101-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-methoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746102-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-biphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746103-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-biphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-746104-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-tolyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-760546-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-fluoro-4-biphenhyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-760547-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-chlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-760548-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-chlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-760549-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-fluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-760552-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-methoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-761114-   8-(2,4-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3,5-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-761115-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-methylthiophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773595-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-methylthiophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773596-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-methoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773597-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-methoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773598-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773658-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-methylthiophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773659-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-methoxyphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-773660-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-hydroxylphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-774117-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-hydroxylphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-774118-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-hydroxylphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-774119-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(4-methylsulfonylphenyl)-8H-pyrido[2,3-d]-pyrimidin-7-one    SB-774120-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(3-methylsulfonylphenyl)-8H-pyrido[2,3-d]-pyrimidin-7-one    SB-774121-   8-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-(2-methylsulfonylphenyl)-8H-pyrido[2,3-d]pyrimidin-7-one    SB-774122-   8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one    SB681323-   3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide    (GSK258899A)-   3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide;    (GSK610677A); or    a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an Ar atmospherewhere necessary.

List of Abbreviations EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride DMAP: 4-(Dimethylamino)pyridine m-CPBA:3-Chlorobenzenecarboperoxoic acid THF: Tetrahydrofuran DCM:Dichloromethane TFA: Trifluoroacetic anhydride HATU:O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate NIS: N-Iodosuccinimide DMF: N,N-DimethylformamideIPA: isopropyl alcohol DSC: differential scanning calorimetry L: litersmL: milliliters mg: milligrams g: grams rt: room temperature eq:equivalents dppf = 1,1′-bis(diphenylphosphino)ferrocene NMP =1-methyl-2-pyrrolidinone dppf: 1,1′-Bis(diphenylphosphino)-ferroceneDMSO: Dimethylsulfoxide EtOAc: Ethyl acetate DIPEA or DIEA:N,N-Diisopropylethylamine SPE: Solid phase extraction MDAP: Massdirected auto preparation HBTU:O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphateHOBT: 1-Hydoxybenzotriazole hydrate HPLC: High Pressure LiquidChromatography M: molar mmol: millimoles mol: moles aq: aqueous eq:equivalents h: hours mp: melting point min: minutes satd: saturated

LC-MS Experimental Conditions: Liquid Chromatograph

System: Shimadzu LC system with SCL-10A Controller and dual UV detectorAutosampler: Leap CTC with a Valco six port injector

Column: Aquasil/Aquasil (C18 40×1 mm)

Inj. Vol.(uL): 2.0

Solvent A: H₂O, 0.02% TFA Solvent B: MeCN, 0.018% TFA

Gradient: linear

Channel A: UV 214 nm Channel B: ELS

Time Dura. Flow Sol. Sol. Step (min) (min) (μL/min) A B 0 0.00 0.00300.00 95.00 5.00 1 0.00 0.01 300.00 95.00 5.00 2 0.01 3.20 300.00 10.0090.00 3 3.21 1.00 300.00 10.00 90.00 4 4.21 0.10 300.00 95.00 5.00 54.31 0.40 300.00 95.00 5.00

Mass Spectrometer: PE Sciex Single Quadrupole LC/MS API-150 Polarity:Positive

Acquisition mode: Profile

General Procedures

Nuclear magnetic resonance spectra were recorded at 400 MHz using on aBruker AC 400 spectrometer. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD (or MeOD) istetradeuteriomethanol. Chemical shifts are reported in parts per million(6) downfield from the internal standard tetramethylsilane (TMS) or theNMR solvent. Abbreviations for NMR data are as follows: s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets,dt=doublet of triplets, app=apparent, br=broad. J indicates the NMRcoupling constant measured in Hertz. Mass spectra were taken on ainstruments, using electrospray (ES) ionization techniques. Alltemperatures are reported in degrees Celsius. Other abbreviations are asdescribed in the ACS Style Guide (American Chemical Society, Washington,D.C., 1986).

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh)silica gel. Preparative hplc were performed using a Gilson PreparativeSystem using a Luna 5u C18(2) 100A reverse phase column eluting with a10-80 gradient (0.1% TFA in acetonitrile/0.1% aqueous TFA) or a 10-80gradient (acetonitrile/water). The CombiFlash system used forpurification in this application was purchased from Isco, Inc.CombiFlash purification was carried out using a prepacked SiO₂ column, adetector with UV wavelength at 254 nm and mixed solvents.

Heating of reaction mixtures with microwave irradiations was carried outon either a Smith Creator (purchased from Personal Chemistry,Forboro/MA, now owned by Biotage), a Emrys Optimizer (purchased fromPersonal Chemistry) or an Explorer (provided by CEM Discover,Matthews/NC) microwave.

Example 14-Chloro-2-methylsulfanyl-8-(4-trifluoromethyl-phenyl)-8H-pyridol[2,3-d]pyrimidin-7-one(SB-776438)

A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde(1.0 g, 4.5 mmol) and Et₃N (1.26 mL, 9.0 mmol) in THF (25 mL) was mixedwith 4-trifluoromethylaniline (0.62 mL, 4.9 mmol). The resultant mixturewas stirred at room temperature for 2 hours beforebis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (0.95 mL,4.5 mmol) was added. After stirring at room temperature for additional12 hours, the mixture was diluted with dichloromethane (50 mL) andwashed with H₂O (2×25 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated. This crude product was further purified bywashing with a mixture of THF/Hexane (1:3, 2×10 mL) to provide the titlecompound (1.17 g, 70%): MS (ES) m/z 372 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.18(s, 3H), 6.79 (d, J=9.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 8.03 (d, J=9.8 Hz, 1H).

Example 24-Chloro-2-methylsulfanyl-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-776439)

A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde(1.0 g, 4.5 mmol) and Et₃N (1.26 mL, 9.0 mmol) in THF (25 mL) was mixedwith 2,4-difluoroaniline (0.50 mL, 4.9 mmol). The resultant mixture wasstirred at room temperature for 2 hours before bis(2,2,2-trifluoroethyl)(methoxycarbonyl-methyl)phosphonate (0.95 mL, 4.5 mmol) was added. Afterstirring at room temperature for additional 48 hours, the mixture wasdiluted with dichloromethane (50 mL) and then washed with H₂O (2×25 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated. Thiscrude product was applied to flash chromatography (EtOAc/Hexane, 1:5) toprovide the title compound (0.79 g, 52%): MS (ES) m/z 340 (M+H)⁺; ¹H-NMR(CDCl₃) δ 2.24 (s, 3H), 6.79 (d, J=9.8 Hz, 1H), 7.06 (m, 2H), 7.29 (m,1H), 8.03 (d, J=9.8 Hz, 1H).

Example 34-Chloro-2-methylsulfanyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-776440)

A solution of4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde(200 mg, 0.63 mmol) in DMF (4.0 mL) and Ac₂O (2.0 mL) was heated with“Smith Creator” (microwave, 160° C.) for 30 minutes. The mixture wasconcentrate under vacuum. Flash chromatography (EtOAc/Hexane, 1:5) thenprovided the title compound (50%): MS (ES) m/z 340 (M+H)⁺; ¹H-NMR(CDCl₃) δ 2.24 (s, 3H), 6.80 (d, J=9.8 Hz, 1H), 7.12 (m, 2H), 7.49 (m,1H), 8.04 (d, J=9.8 Hz, 1H).

Example 44-Chloro-2-methylsulfinyl-8-(4-trifluoromethyl-phenyl)-8H-pyridol[2,3-d]pyrimidin-7-one(SB-776441)

A solution of4-Chloro-2-methylsulfanyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(1.0 g, 2.7 mmol) in dichloromethane (50 mL) was mixed with m-CPBA (0.63g, 4.0 mmol). The resultant mixture was stirred at room temperature for10 minutes and concentrated under vacuum. Flash chromatography(EtOAc/Hexane, 3:1) then provided the title compound (0.86 g, 82%): MS(ES) m/z 388 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.80 (s, 3H), 7.03 (d, J=9.9 Hz,1H), 7.39 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 8.19 (d, J=9.9 Hz,1H).

Example 54-Chloro-2-methylsulfinyl-8-(2,4-difluoro-phenyl)-8H-pyridol[2,3-d]pyrimidin-7-one(SB-776442)

A solution of4-Chloro-2-methylsulfanyl-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(1.0 g, 2.9 mmol) in dichloromethane (50 mL) was mixed with m-CPBA (0.69g, 4.4 mmol). The resultant mixture was stirred at room temperature for10 minutes and concentrated under vacou. Flash chromatography(EtOAc/Hexane, 3:1) then provided the title compound (1.02 g, 97%): MS(ES) m/z 356 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.84 (m, 3H), 7.01 (d, J=9.9 Hz,1H), 7.09 (m, 2H), 7.29 (m, 1H), 8.16 (d, J=9.9 Hz, 1H).

Example 64-Chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-776443)

A solution of4-Chloro-2-methylsulfanyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(1.0 g, 2.9 mmol) in dichloromethane (50 mL) was mixed with m-CPBA (0.69g, 4.4 mmol). The resultant mixture was stirred at room temperature for10 minutes and concentrated under vacou. Flash chromatography(EtOAc/Hexane, 3:1) then provided the title compound (0.91 g, 87%): MS(ES) m/z 356 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.85 (s, 3H), 7.03 (d, J=9.6 Hz,1H), 7.15 (m, 2H), 7.53 (m, 1H), 8.18 (d, J=9.6 Hz, 1H).

Example 74-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-776444)

A solution of4-Chloro-2-methylsulfinyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(0.29 g, 0.75 mmol) in dichloromethane (30 mL) was mixed with a solutionof serinol (0.075 g, 0.82 mmol) in DMF (0.75 mL). The resultant mixturewas stirred at room temperature for 1 hour before concentrated undervacuum. Flash chromatography (EtOAc:Hexane, 3:1) then provided the titlecompound (0.14 g, 45%): MS (ES) m/z 415 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.25(s, br, 2H), 3.66 (m, br, 5H), 6.15 (m, br, 1H), 6.55 (d, J=9.2 Hz, 1H),7.36 (m, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.2 Hz, 1H).

Example 84-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-776445)

A solution of4-Chloro-2-methylsulfinyl-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(0.24 g, 0.67 mmol) in dichloromethane (24 mL) was mixed with a solutionof serinol (0.065 g, 0.71 mmol) in DMF (0.65 mL). The resultant mixturewas stirred at room temperature for 1 hour before concentrated undervacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the titlecompound (0.12 g, 46%): MS (ES) m/z 383 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.15(s, br, 2H), 3.75 (m, br, 5H), 6.10 (m, br, 1H), 6.55 (m, 1H), 7.04 (m,2H), 7.28 (m, 1H), 7.90 (m, 1H).

Example 94-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-776446)

A solution of4-Chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(0.90 g, 2.53 mmol) in dichloromethane (90 mL) was mixed with a solutionof serinol (0.24 g, 2.66 mmol) in DMF (2.0 mL). The resultant mixturewas stirred at room temperature for 1 hour before concentrated undervacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the titlecompound (0.40 g, 42%): MS (ES) m/z 383 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.95(s, br, 2H), 3.90 (m, br, 5H), 6.05 (m, br, 1H), 6.56 (d, J=9.6 Hz, 1H),7.10 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.94 (d, J=9.6 Hz, 1H).

Example 104-(2-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-739796)

A solution of4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(50 mg, 0.12 mmol) in dioxane/H₂O (3:1, 4.8 mL) was mixed with2-methylthiophenyl boronic acid (30.4 mg, 0.18 mmol) and K₂CO₃ (50.1 mg,0.36 mmol). The resultant mixture was bubbled with argon for 5 minutes,and added by Pd(PPh₃)₄ (2.8 mg, 0.0024 mmol). The reaction tube wassealed and heated with “Smith Creator” (microwave, 150° C.) for 15minutes. The mixture was concentrated under vaco. Flash chromatography(EtOAc/Hexane, 3:1) then provided the title compound (88%): MS (ES) m/z503 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.48 (s, 3H), 2.65 (s, br, 2H), 3.70 (m,br, 5H), 6.20 (m, br, 1H), 6.45 (m, 1H), 7.43 (m, 6H), 7.68 (m, 1H),7.83 (m, 2H).

Example 114-(3-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-739804)

The title compound was prepared by following the procedure in Example 10except 3-methylthiophenyl boronic acid was used in the coupling step(76%): MS (ES) m/z 503 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.49 (s, br, 2H), 2.54(s, 3H), 3.68 (m, br, 5H), 5.90 (s, br, 1H), 6.47 (s, b, 1H), 7.45 (m,6H), 7.65 (m, 1H), 7.82 (m, 2H).

Example 124-(4-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-740717)

The title compound was prepared by following the procedure in Example 10except 4-methylthiophenyl boronic acid was used in the coupling step(56%): MS (ES) m/z 503 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.40 (s, br, 2H), 2.58(s, 3H), 3.69 (m, br, 5H), 5.85 (s, br, 1H), 6.48 (m, 1H), 7.40 (m, 2H),7.48 (m, 2H), 7.56 (m, 2H), 7.67 (m, 1H), 7.83 (m, 2H).

Example 134-phenyl-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-741658)

The title compound was prepared by following the procedure in Example 10except phenyl boronic acid was used in the coupling step (82%): MS (ES)m/z 457 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.81 (s, br, 2H), 3.68 (m, br, 5H),6.10 (m, br, 1H), 6.47 (m, 1H), 7.40 (m, 2H), 7.59 (m, 5H), 7.82 (m,3H).

Example 144-(3-chlorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-741922)

The title compound was prepared by following the procedure in Example 10except 3-chlorophenyl boronic acid was used in the coupling step (76%):MS (ES) m/z 491 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.66 (s, br, 2H), 3.73 (m, br,5H), 6.15 (m, br, 1H), 6.50 (m, 1H), 7.52 (m, 6H), 7.75 (m, 1H), 7.84(m, 2H).

Example 154-(4-chlorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-741923)

The title compound was prepared by following the procedure in Example 10except 4-chlorophenyl boronic acid was used in the coupling step (72%):MS (ES) m/z 491 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.61 (s, br, 2H), 3.73 (m, br,5H), 6.05 (m, br, 1H), 6.50 (m, 1H), 7.41 (m, 2H), 7.58 (m, 4H), 7.76(m, 1H), 7.84 (m, 2H).

Example 164-(3,4-difluorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-742172)

The title compound was prepared by following the procedure in Example 10except 3,4-difluorophenyl boronic acid was used in the coupling step(65%): MS (ES) m/z 493 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.06 (s, br, 2H), 3.72(m, br, 5H), 6.05 (m, br, 1H), 6.50 (m, 1H), 7.42 (m, 5H), 7.76 (m, 1H),7.83 (m, 2H).

Example 174-(2-Chlorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-74364)

The title compound was prepared by following the procedure in Example 10except 2-chlorophenyl boronic acid was used in the coupling step (72%).MS (ES) m/z 491 (M+H)⁺; ¹H-NMR (CDCl₃) δ 3.60 (m, br, 5H), 6.10 (m, br,1H), 6.45 (m, 1H), 7.32 (m, 2H), 7.50 (m, 5H), 7.80 (m, 2H).

Example 184-(4-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-742501)

The title compound was prepared by following the procedure in Example 10except [4-(methyloxy)phenyl]boronic acid was used in the coupling step(66%). MS (ES) m/z 487 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.85 (s, br, 2H), 3.69(m, br, 5H), 3.92 (s, 3H), 6.10 (m, br, 1H), 6.47 (m, 1H), 7.07 (m, 2H),7.40 (m, 2H), 7.60 (m, 2H), 7.84 (m, 3H).

Example 194-(3-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-742502)

The title compound was prepared by following the procedure in Example 10except [3-(methyloxy)phenyl]boronic acid was used in the coupling step(65%): MS (ES) m/z 487 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.90 (s, br, 2H), 3.61(m, br, 5H), 3.88 (s, 3H), 6.05 (m, br, 1H), 6.45 (m, 1H), 7.09 (m, 2H),7.45 (m, 4H), 7.80 (m, 3H).

Example 204-(2-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-742503)

The title compound was prepared by following the procedure in Example 10except [2-(methyloxy)phenyl]boronic acid was used in the coupling step(75%): MS (ES) m/z 487 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.20 (s, br, 2H), 3.69(m, br, 5H), 3.84 (s, 3H), 6.05 (m, br, 1H), 6.41 (m, 1H), 7.12 (m, 2H),7.47 (m, 5H), 7.83 (m, 2H).

Example 214-(3-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-743869)

A solution of4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(50 mg, 0.13 mmol) in dioxane/H₂O (3:1, 4.8 mL) was mixed with3-methylthiophenyl boronic acid (33.8 mg, 0.20 mmol) and K₂CO₃ (54.3 mg,0.39 mmol). The resultant mixture was bubbled with argon for 5 minutesfollowed by the addition of Pd(PPh₃)₄ (3.0 mg, 0.0026 mmol). Thereaction tube was sealed and heated with “Smith Creator” (microwave,150° C.) for 15 minutes. The mixture was concentrated under vaco. Flashchromatography (EtOAc/Hexane, 3:1) then provided the title compound(90%): MS (ES) m/z 471 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.40 (s, br, 2H), 2.40(s, 3H), 3.90 (m, br, 5H), 6.00 (m, br, 1H), 6.45 (m, 1H), 7.15 (m, 2H),7.40 (m, 5H), 7.85 (m, 1H).

Example 224-(4-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746098)

The title compound was prepared by following the procedure in Example 21except 4-methylthiophenyl boronic acid was used in the coupling step(95%): MS (ES) m/z 471 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.35 (s, br, 2H), 2.57(s, 3H), 3.76 (m, br, 5H), 6.05 (m, br, 1H), 6.46 (m, 1H), 7.05 (m, 2H),7.27 (m, 1H), 7.39 (m, 2H), 7.55 (m, 2H), 7.81 (m, 1H).

Example 234-(2-methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746099)

The title compound was prepared by following the procedure in Example 21except 2-methylthiophenyl boronic acid was used in the coupling step(72%): MS (ES) m/z 471 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.45 (s, 3H), 2.55 (s,br, 2H), 3.72 (m, br, 5H), 6.05 (m, br, 1H), 6.40 (m, 1H), 7.05 (m, 2H),7.40 (m, 6H).

Example 244-(3,4-di/fluorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746100)

The title compound was prepared by following the procedure in Example 21except 3,4-difluorophenyl boronic acid was used in the coupling step(56%): MS (ES) m/z 461 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.25 (s, br, 2H), 3.77(m, br, 5H), 6.15 (m, br, 1H), 6.48 (m, 1H), 7.06 (m, 2H), 7.49 (m, 4H),7.74 (m, 1H).

Example 254-(2-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746101)

The title compound was prepared by following the procedure in Example 21except 2-methoxyphenyl boronic acid was used in the coupling step (89%):MS (ES) m/z 455 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.85 (s, br, 2H), 3.67 (m, br,5H), 3.81 (s, 3H), 6.10 (m, br, 1H), 6.38 (m, 1H), 7.07 (m, 5H), 7.30(s, 1H), 7.38 (m, 1H), 7.50 (m, 1H).

Example 264-(4-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746102)

The title compound was prepared by following the procedure in Example 21except 4-methoxyphenyl boronic acid was used in the coupling step (70%):MS (ES) m/z 455 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.60 (s, br, 2H), 3.73 (m, br,5H), 3.91 (s, 3H), 6.15 (m, br, 1H), 6.45 (m, 1H), 7.05 (m, 4H), 7.38(s, 1H), 7.58 (m, 2H), 7.83 (m, 1H).

Example 274-(2-Biphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746103)

The title compound was prepared by following the procedure in Example 21except 2-biphenyl boronic acid was used in the coupling step (89%): MS(ES) m/z 501 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.06 (s, br, 2H), 3.73 (m, br,5H), 6.15 (m, br, 1H), 6.18 (s, br, 1H), 7.00 (m, 2H), 7.25 (m, 7H),7.58 (m, 4H).

Example 284-(3-Biphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-746104)

The title compound was prepared by following the procedure in Example 21except 3-biphenyl boronic acid was used in the coupling step (92%): MS(ES) m/z 501 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.10 (s, br, 2H), 3.72 (m, br,5H), 6.10 (m, br, 1H), 6.47 (m, 1H), 7.06 (m, 2H), 7.60 (m, 8H), 7.82(m, 3H).

Example 294-(2-Tolyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-760546)

The title compound was prepared by following the procedure in Example 21except 2-tolyl boronic acid was used in the coupling step (66%): MS (ES)m/z 439 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.24 (s, 3H), 2.96 (s, br, 2H), 3.68(m, br, 5H), 6.10 (m, br, 1H), 6.39 (m, 1H), 7.04 (m, 2H), 7.40 (m, 6H).

Example 304-(3-Fluoro-4-biphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-760547)

The title compound was prepared by following the procedure in Example 21except 3-fluoro-4-biphenyl boronic acid was used in the coupling step(48%): MS (ES) m/z 519 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.15 (s, br, 2H), 3.78(m, br, 5H), 6.05 (m, br, 1H), 6.50 (m, 1H), 7.06 (m, 2H), 7.28 (m, 1H),7.52 (m, 8H), 7.86 (m, 1H).

Example 314-(4-Chlorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-760548)

The title compound was prepared by following the procedure in Example 21except 4-chlorophenyl boronic acid was used in the coupling step (70%):MS (ES) m/z 459 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.83 (s, br, 2H), 3.72 (m, br,5H), 6.15 (m, br, 1H), 6.46 (m, 1H), 7.04 (m, 2H), 7.28 (m, 1H), 7.53(m, 4H), 7.72 (m, 1H).

Example 324-(3-Chlorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-760549)

The title compound was prepared by following the procedure in Example 21except 3-chlorophenyl boronic acid was used in the coupling step (49%).MS (ES) m/z 459 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.55 (s, br, 2H), 3.74 (m, br,5H), 6.10 (m, br, 1H), 6.47 (m, 1H), 7.05 (m, 2H), 7.28 (m, 1H), 7.53(m, 4H), 7.73 (m, 1H).

Example 334-(3-Fluorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-760552)

The title compound was prepared by following the procedure in Example 21except 3-fluorophenyl boronic acid was used in the coupling step (64%):MS (ES) m/z 443 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.05 (s, br, 2H), 3.79 (m, br,5H), 6.10 (m, br, 1H), 6.49 (m, 1H), 7.07 (m, 2H), 7.42 (m, 5H), 7.77(m, 1H).

Example 344-(3-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-761114)

The title compound was prepared by following the procedure in Example 21except 3-methoxyphenyl boronic acid was used in the coupling step (89%):MS (ES) m/z 455 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.07 (s, br, 2H), 3.83 (m, br,5H), 3.91 (s, 3H), 6.15 (m, br, 1H), 6.47 (m, 1H), 7.10 (m, 5H), 7.28(m, 1H), 7.47 (m, 1H), 7.82 (m, 1H).

Example 354-(3,5-Difluorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-761115)

The title compound was prepared by following the procedure in Example 21except 3,5-difluorophenyl boronic acid was used in the coupling step(89%): MS (ES) m/z 461 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.05 (s, br, 2H), 3.89(m, br, 5H), 6.10 (m, br, 1H), 6.51 (m, 1H), 7.08 (m, 5H), 7.28 (m, 1H),7.75 (m, 1H).

Example 364-(2-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773595)

A solution of4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(50 mg, 0.13 mmol) in dioxane/H₂O (3:1, 4.8 mL) was mixed with2-methylthiophenyl boronic acid (33.8 mg, 0.20 mmol) and K₂CO₃ (54.3 mg,0.39 mmol). The resultant mixture was bubbled with argon for 5 minutes,and added by Pd(PPh₃)₄ (3.0 mg, 0.0026 mmol). The reaction tube wassealed and heated with “Smith Creator” (microwave, 150° C.) for 15minutes. The mixture was concentrated under vaco. Flash chromatography(EtOAc/Hexane, 3:1) then provided the title compound (89%): MS (ES) m/z471 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.45 (s, 3H), 2.55 (s, br, 2H), 3.72 (m,br, 5H), 6.25 (m, br, 1H), 6.41 (m, 1H), 7.11 (m, 2H), 7.30 (m, 2H),7.45 (m, 2H), 7.51 (m, 2H).

Example 374-(3-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773596)

The title compound was prepared by following the procedure in Example 36except 3-methylthiophenyl boronic acid was used in the coupling step(71%): MS (ES) m/z 471 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.50 (s, br, 2H), 2.55(s, 3H), 3.72 (m, br, 5H), 6.25 (m, br, 1H), 6.47 (m, 1H), 7.11 (m, 2H),7.35 (m, 1H), 7.46 (m, 4H), 7.77 (m, 1H).

Example 384-(4-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773597)

The title compound was prepared by following the procedure in Example 36except 4-methoxyphenyl boronic acid was used in the coupling step (70%):MS (ES) m/z 455 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.80 (s, br, 2H), 3.77 (m, br,5H), 3.92 (s, 3H), 6.10 (m, br, 1H), 6.47 (m, 1H), 7.12 (m, 4H), 7.50(m, 1H), 7.62 (m, 2H), 7.86 (m, 1H).

Example 394-(3-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773598)

The title compound was prepared by following the procedure in Example 36except 3-methoxyphenyl boronic acid was used in the coupling step (79%):MS (ES) m/z 455 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.25 (s, br, 2H), 3.75 (m, br,5H), 3.90 (s, 3H), 6.15 (m, br, 1H), 6.46 (m, 1H), 7.15 (m, 5H), 7.47(m, 2H), 7.82 (m, 1H).

Example 404-phenyl-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773658)

The title compound was prepared by following the procedure in Example 36except phenyl boronic acid was used in the coupling step (89%): MS (ES)m/z 425 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.16 (s, br, 2H), 3.83 (m, br, 5H),6.15 (m, br, 1H), 6.47 (m, 1H), 7.13 (m, 2H), 7.55 (m, 6H), 7.80 (m,1H).

Example 414-(4-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773659)

The title compound was prepared by following the procedure in Example 36except 4-methylthiophenyl boronic acid was used in the coupling step(67%): MS (ES) m/z 471 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.50 (s, 3H), 2.57 (s,br, 2H), 3.72 (m, br, 5H), 6.20 (m, br, 1H), 6.46 (m, 1H), 7.11 (m, 2H),7.39 (m, 2H), 7.45 (m, 1H), 7.56 (m, 2H), 7.81 (m, 1H).

Example 424-(2-Methoxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-773660)

The title compound was prepared by following the procedure in Example 36except 2-methoxyphenyl boronic acid was used in the coupling step (91%):MS (ES) m/z 455 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.70 (s, br, 2H), 3.68 (m, br,5H), 3.82 (s, 3H), 6.20 (m, br, 1H), 6.40 (m, 1H), 7.08 (m, 4H), 7.48(m, 4H).

Example 434-(2-Hydroxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-774117)

A solution of4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(50 mg, 0.13 mmol) in dioxane/H₂O (3:1, 4.8 mL) was mixed with2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (44.0 mg, 0.20mmol) and K₂CO₃ (71.9 mg, 0.52 mmol). The resultant mixture was bubbledwith argon for 5 minutes, and added by Pd(PPh₃)₄ (3.0 mg, 0.0026 mmol).The reaction tube was sealed and heated with “Smith Creator” (microwave,150° C.) for 15 minutes. The mixture was concentrated under vaco. Flashchromatography (EtOAc/Hexane, 3:1) then afforded the title compound(82%): MS (ES) m/z 441 (M+H)⁺; ¹H-NMR (CDCl₃) δ 1.65 (s, br, 2H), 3.80(m, br, 5H), 6.05 (m, br, 1H), 6.54 (m, 1H), 7.15 (m, 4H), 7.48 (m, 3H),7.98 (m, 1H).

Example 444-(3-Hydroxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-774118)

The title compound was prepared by following the procedure in Example 43except 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used inthe coupling step (13%): MS (ES) m/z 441 (M+H)⁺; ¹H-NMR-(CD₃OD) δ 2.18(m, br, 5H), 4.92 (m, 1H), 5.50 (m, 1H), 5.65 (m, 4H), 5.86 (m, 1H),6.08 (m, 1H), 6.44 (m, 1H).

Example 454-(4-Hydroxyphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-774119)

The title compound was prepared by following the procedure in Example 43except 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used inthe coupling step (56%): MS (ES) m/z 441 (M+H)⁺; ¹H-NMR (CD₃OD) δ 2.18(m, br, 5H), 4.91 (m, 1H), 5.48 (m, 2H), 5.71 (m, 2H), 6.07 (m, 3H),6.51 (m, 1H).

Example 464-(4-Methylsulfonyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-774120)

A solution of4-(4-Methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(50 mg, 0.11 mmol) in methylene chloride (3 mL) was mixed with mCPBA(80.0 mg, 0.33 mmol). After stirring at room temperature for 30 minutes,the mixture was concentrated under vaco. Flash chromatography(EtOAc/Hexane, 10:1) then provided the title compound (61%): MS (ES) m/z502 (M+H)⁺; ¹H-NMR (CDCl₃) δ 2.06 (s, br, 2H), 3.16 (s, 3H), 3.77 (m,br, 5H), 6.20 (m, br, 1H), 6.51 (m, 1H), 7.13 (m, 2H), 7.51 (m, 1H),7.68 (m, 1H), 7.85 (m, 2H), 8.15 (m, 2H).

Example 474-(3-Methylsulfonyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-774121)

The title compound was prepared from4-(3-methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-oneby following the procedure in Example 46 (64%): MS (ES) m/z 503 (M+H)⁺;¹H-NMR (CDCl₃) δ 2.09 (s, br, 2H), 3.16 (s, 3H), 3.78 (m, br, 5H), 6.35(m, br, 1H), 6.55 (m, 1H), 7.14 (m, 2H), 7.50 (m, 1H), 7.70 (m, 1H),7.81 (m, 1H), 7.95 (m, 1H), 8.17 (m, 1H), 8.30 (s, br, 1H).

Example 484-(2-Methylsulfonyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one(SB-774122)

The title compound was prepared from4-(2-methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-oneby following the procedure in Example 46 (62%): MS (ES) m/z 503 (M+H)⁺;¹H-NMR (CDCl₃) δ 2.27 (s, br, 2H), 3.28 (s, 3H), 3.77 (m, br, 5H), 6.20(s, br, 1H), 6.41 (m, 1H), 7.13 (m, 2H), 7.25 (m, 1H), 7.48 (m, 2H),7.81 (m, 2H), 8.26 (m, 1H).

Example 49N-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzamide(GSK174908A)

3-Fluoro-4-methylbenzoic acid (1.54 g, 0.01 mol) is dissolved intrifluoromethanesulfonic acid (10 mL) and cooled to about 0° C. NIS(2.25 g. 0.01 mol) is added in several portions over a 6 h period whilemaintaining the reaction temperature at about 0° C. The mixture isallowed to warm to rt. overnight. The reaction mixture is then pouredover ice and extracted with ethyl acetate (3×). The organic layers arewashed (Na₂S₂O₅) and concentrated. The material is carried on crude.

The crude acid from above (−1.5 g) is dissolved in thionyl chloride (75mL) and heated to 80° C. for about 2 h. The mixture is then cooled toroom temperature and stirred under N₂ overnight. The mixture isconcentrated in vacuo and dissolved in 15 mL DCM. Na₂CO₃ (3 g) is addedalong with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter“mol”)). The mixture is allowed to stir overnight and purified via flashchromatography (5% MeOH/CH₂Cl₂) to afford 0.904 g ofN-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide

N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (0.904 g, 2.83 mmol) isdissolved in DMF (30 mL). Bis-pinicalato-diborane (1.44 g, 2.83 mmol) isadded followed by PdCl₂.dppf (55 mg) and potassium acetate (1.38 g,14.15 mmol). The mixture are stirred for about 18 h, concentrated invacuo and purified via flash chromatography to affordN-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(60 mg).

4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one(0.056 g, 0.17 mmol),N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(0.065 g, 0.17 mmol), K₂CO₃ (0.07 g, 0.51 mmol) and tetrakis triphenylphosphine palladium (10 mg, 0.05 eq) are dissolved in dioxane/water(3:1, 10 mL) and heated to about 100° C. for about 3 h. The mixture isconcentrated and purified via reverse phase HPLC to afford the titlecompound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)⁺,1.69 min (ret time). HPLC indicates 96% pure.

Example 504-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Intermediate 150b from pu61314)

To the compound4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one(1.59 g, 4.47 mmol) in dichloromethane (89.4 mL) were addedN,N-diethyl-1,3-propanediamine (0.845 mL, 5.36 mol) and triethylamine(1.26 uL, 8.94 mmol). The mixture was stirred at rt overnight. Somewhite precipitate was formed during the reaction. Filtration followed bywash with ethyl acetate/dichoromethane/methnol afforded the titlecompound (1.028 g, 60%). LC-MS m/z 383 (M+H)⁺.

Example 514-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-oneIntermediate 163a from PU61314)

To the compound4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(1.39 g, 3.9 mmol) in dichloromethane (80 mL) were added4-methyl-1,4′-bipiperidine (0.75 g, 5.85 mol) and triethylamine (1.03mL, 11.7 mmol). The mixture was stirred at about −20° C. overnight.Filtration followed by concentration, the crude was purified with flashchromatography to afford the title compound (0.904 g, 51%). LC-MS m/z474 (M+H)⁺.

Example 523-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoicAcid (GSK1080365A)

To a stirring solution of 3-iodo-4-methylbenzoic acid (60 g, 0.22 mol, 1eq) in degassed DMF (1400 mL, 23.3 vol.) was charged4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (81.4 g, 0.32mol, 1.4 eq) followed by potassium acetate (112 g, 1.14 mole, 5 eq) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18.7 g,0.02 mole, 0.1 eq). The resulting mixture was placed under a nitrogenatmosphere and was heated to 80° C. with the exclusion of lightovernight. The mixture was then concentrated under high vacuum and theresidue partitioned between EtOAc and 2M HCl. The mixture was thenfiltered and the layers separated. The aqueous phase was re-extractedwith EtOAc. The combined organics were then washed with brine, dried andevaporated to yield a brown solid that was applied to a silica plug theneluted with 2:1 cyclohexane:ethyl acetate. Fractions were then combinedand evaporated to yield a brown foam that was triturated withcyclohexane, collected by filtration then dried in vacuo to yield4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. δ(CDCl₃) 8.50-8.49 (1H, d), 8.04-8.02 (1H, dd), 7.27-7.25 (1H, d), 2.61(3H, s), 1.36 (12H, s).

To the compound4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(47.5 mg, 0.1 mmol) in dioxane (3 mL) and water (1 mL) were added4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(38.4 mg, 0.15 mol), potassium carbonate (83 mg, 0.6 mmol) andtetrakis(triphenylphosphine)palladium(0) (4.6 mL, 0.005 mmol). Themixture was heated with microwave at about 150° C. for about 15 min. Themixture was concentrated & then mixed with DMSO (0.75 mL) and water(0.25 mL). Separation by HPLC afforded the title compound (39 mg, 68%).LC-MS m/z 574 (M+H)⁺.

Example 533-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoicAcid (Intermediate 150c from PU61314)

To the compound4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one(176 mg, 0.418 mmol) in dioxane (4.5 mL) and water (1.5 mL) was added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(173 mg, 0.626 mol), potassium carbonate (289 mg, 2.09 mmol) andtetrakis(triphenylphosphine)palladium(0) (24.2 mg, 0.0259 mmol). Themixture was heated with microwave at about 150° C. for about 15 min. Themixture was filtered. Separation by HPLC with TFA afforded the titlecompound (238 mg, 99%). LC-MS m/z 522 (M+H)⁺.

Example 54 1,1-dimethylethyl3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoatetrifluoroacetate (Intermediate 179a from PU61314)

To the compound4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one(600 mg, 1.422 mmol) in dioxane (15 mL) and water (5 mL) were added1,1-dimethylethyl3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(542 mg, 2.132 mol), potassium carbonate (590 mg, 4.26 mmol) andtetrakis(triphenylphosphine)-palladium(0) (82 mg, 0.071 mmol). Themixture was heated with microwave at 150° C. for 15 minutes. The mixturewas filtered. Separation by HPLC with TFA afforded the crude titlecompound.

Example 554-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoicAcid (GSK1132145A)

To the compound4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one(168.75 mg, 0.40 mmol) in dioxane (12 mL) and water (4 mL) were added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (148.85 mg,0.60 mol), potassium carbonate (208 mg, 1.20 mmol) andtetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). The mixturewas heated with microwave at 150° C. for 15 min. The mixture wasconcentrated. It was mixed with DMSO (0.75 mL) and water (0.25 mL).Separation by HPLC afforded the title compound (147 mg, 72%). LC-MS m/z508 (M+H)⁺.

Example 563-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoicAcid (GSK1120344A)

To the compound4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one(210.5 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (125 mg,0.75 mol), potassium carbonate (210 mg, 1.20 mmol) andtetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). Themixture was heated with microwave at about 150° C. for about 15 min. Themixture was concentrated, then mixed with DMSO (0.75 mL) and water (0.25mL). Separation by HPLC afforded the title compound (467 mg, 32%). LC-MSm/z 508 (M+H)⁺.

Example 575-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(GW797371X) 57a)4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile(SB-666443)

To the solution of phosphorus oxychloride (65 mL, 0.70 mol) intrichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly tokeep the temperature between 5° C. to 10° C. The solution was thenwarmed up to room temperature before6-hydroxy-2-(methylthio)-4(1H)-pyrimidinone (25 g, 0.16 mol) was addedin portions. The resultant reaction mixture was heated at 80° C.overnight followed by concentration under vacuum. The resulting slurrylike residue was poured into ice, stirred for about 2 hours thenfiltered to afford the crude product. The crude product was furtherpurified by recrystallization with hexane to afford4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g, 61%).¹H-NMR (CDCl₃) δ 2.66 (s, 3H), 10.4 (s, 1H).

To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc(0.113 mL, 2.0 mmol) and EtOH (5 mL) was added4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (223 mg, 1.0 mol)to room temperature. The solution was then heated at 50° C. for about 1hour, 60° C. for about 30 minutes and 70° C. for about 30 minutes beforeit was concentrated under vacuum and washed with H₂O (10-20 mL) toafford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190mg, 80%). LC-MS m/z 238 (M+H)⁺ 1.57 minute, 1.65 minute; ¹H-NMR (CDCl₃)δ 2.62, 2.65 (3H), 7.53, 8.30 (1H).

To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g,10 mmol) was added SOCl₂ (21.8 mL, 0.30 mol) slowly at room temperature.The solution was then heated at 75° C. for about 3 hours before it wasconcentrated under vacuum. The residue SOCl₂ was removed by evaporationwith toluene (5 mL) under vacuum. The resulting solid was washed withEtOH/H₂O (10 mL, 1:1) to afford4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.04 g, 93%).LC-MS m/z 220 (M+H)⁺ 1.99 minute; ¹H-NMR (CDCl₃) δ 2.64 (3H).

To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile(2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17mL, 20.0 mmol). The solution was stirred at 50° C. for about 60 minutes.The mixture was slowly added into a solution of MeOH (20 mL) and water(30 mL). The resultant solid was filtered and washed with MeOH/H₂O (20mL, 1:1) to give4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrileas a white solid (2.82 g, 90%). LC-MS m/z 313 (M+H)⁺; ¹H-NMR (CDCl₃) δ2.33 (s, 3H), 6.94 (s, 1H), 7.04 (m, 2H), 7.35 (m, 1H).

57b)5-(Aminomethyl)-6-chloro-N-(2,6-difluorophenyl)-2-(methylthio)-4-pyrimidinamine(Intermediate 1b from PU61344)

To the solution of4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile(0.938 g) was added borane.THF complex (1.0 M, 15 mL). The reactionmixture was then heated at reflux for about 4 h until all the startingmaterial disappeared. The solution was cooled to r.t., mixed with HClsolution (6 M, 5 mL), and stirred at room temperature for about 30minutes. The solution was then mixed with NaOH solution (3 M) to pH9.0-10.0. The organic phase was separated and the aqueous layer wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (50 mL), collected, dried over Na₂SO₄ and concentrated toafford the title compound 0.97 g (quantative). LC-MS m/z 317 (M+H)⁺, 1.5min (ret. time).

57c)5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[1,5-d]pyrimidin-2(1H)-one(GW797371X)

To the solution of5-(aminomethyl)-6-chloro-N-(2,6-difluorophenyl)-2-(methylthio)-4-pyrimidinamine(0.317 g) in CH₂Cl₂ (5 mL) was added the mixture of carbonyl diimidazole(0.178 g) in CH₂Cl₂ (5 mL). The resultant mixture was stirred for about3 hours at r.t., mixed with CH₂Cl₂ (10 mL) and washed with HCl (1 N,2×10 mL) and H₂O (20 mL). The organic layers were collected, dried overNa₂SO₄, filtered and concentrated to provide the title compound (0.279g, 81%). LC-MS m/z 343 (M+H)⁺, 1.75 min (ret. time); ¹H-NMR (400 MHz,CDCl₃) δ 7.44-7.40 (m, 1H), 7.07-7.03 (m, 2H), 5.84 (br, 1H), 4.62 (s,2H), 2.19 (s, 3H).

Example 585-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(Intermediate 86a from PU61344)

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (1.71 g, 5 mmol) in CH₂Cl₂ (60 mL) was added m-CPBA (1.17 g, 5.2mmol). The mixture was stirred at room temperature for 10 minutes, thendirectly loaded onto a column. Flash chromatography (mobile phaseEtOAc/Hexane) afforded the title compound as a white solid 1.58 g (88%).LC-MS m/z 358 (M+H)⁺.

Example 595-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(Intermediate 86b from PU61344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(250 mg, 0.70 mmol) in DCM (10 mL) were added4-(1-pyrrolidinyl)piperidine (323 mg, 2.1 mmol) andN,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (253 mg, 81%). LC-MS m/z 449 (M+H)+

Example 603-{8-(2,6-difluorophenyl)-7-oxo-2-[4-(1-pyrrolidinyl)-1-piperidinyl]-5,6,7,8-tetrhahdropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide(GSK867059A)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-]pyrimidin-2(1H)-one(18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were addedpotassium carbonate (34 mg, 0.25 mmol),tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) andN-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(22 mg, 0.062 mmol). The reaction mixture was bubbled with N₂ for 5mins, then microwaved at about 150° C. for about 30 mins. The reactionmixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (14 mg, 54%). LC-MS m/z 642 (M+H)⁺; ¹H-NMR (CD₃OD) δ 1.32 (m, 2H),1.80 (m, 4H), 1.88 (m, 2H), 2.24 (m, 1H), 2.33 (s, 3H), 2.62 (m, 4H),2.74 (t, 2H), 4.17 (m, 2H), 4.40 (m, 2H), 7.12 (m, 4H), 7.52 (m, 2H),7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 617-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(87a from PU61344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.56 mmol) in DCM (10 mL) were added 1,4′-bipiperidine (270 mg,1.61 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (298 mg, 83%). LC-MS m/z 463 (M+H)⁺.

Example 623-[2-(1,4′-bipiperidin-1′-yl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(GSK867060A)

To a solution of compound7-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were addedpotassium carbonate (34 mg, 0.25 mmol),tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) andN-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(22 mg, 0.062 mmol). The reaction mixture was bubbled with N₂ for 5mins, then microwaved at about 150° C. for about 30 mins. The reactionmixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH [7]+NH₄OH[3]) provided the title compound as a whitesolid (13 mg, 51%). LC-MS m/z 656 (M+H)⁺; ¹H-NMR (CD₃OD) δ 1.37 (m, 2H),1.48 (m, 2H), 1.60 (m, 4H), 1.80 (m, 2H), 2.33 (s, 3H), 2.56 (m, 5H),2.72 (t, 2H), 4.17 (m, 2H), 4.46 (m, 2H), 7.12 (m, 4H), 7.52 (m, 2H),7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 635-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(Example 88a of PU61344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(800 mg, 2.23 mmol) in DCM (45 mL) were addedN,N-dimethylethylenediamine (0.36 mL, 3.23 mmol) and triethylamine (0.63mL, 4.5 mmol). The resultant solution was stirred at room temperatureover night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (730 mg, 85%). LC-MS m/z 383 (M+H)⁺.

Example 643-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicAcid (88b of PU61344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)-ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(100 mg, 0.26 mmol) in dioxane (9 mL)/water (3 mL) were added potassiumcarbonate (217 mg, 1.57 mmol), tetrakis(triphenylphosphine)palladium(0)(15 mg, 0.013 mmol) and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (65 mg, 0.39mmol). The reaction mixture was bubbled with N₂ for 5 mins, thenmicrowaved at about 150° C. for about 30 mins. The reaction mixture wasconcentrated. To the concentrated mixture were added DMSO (2 mL), H₂O(0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided thetitle compound as a white solid (120 mg, 98%). LC-MS m/z 469 (M+H)⁺.

Example 654-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicAcid (96a of PU6.1344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)-ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(150 mg, 0.39 mmol) in dioxane (12 mL)/water (4 mL) were added potassiumcarbonate (325 mg, 2.36 mmol), tetrakis(triphenylphosphine)palladium(0)(23 mg, 0.019 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (146 mg,0.59 mmol). The reaction mixture was bubbled with N₂ for about 5 mins,then microwaved at about 150° C. for about 30 mins. The reaction mixturewas concentrated. To the concentrated mixture were added DMSO (2 mL),H₂O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided thetitle compound as a white solid (142 mg, 77%). LC-MS m/z 469 (M+H)_(v).

Example 664-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahadropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicAcid (Example 104b of PU61344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.52 mmol) in dioxane (15 mL)/water (5 mL) were added potassiumcarbonate (433 mg, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0)(31 mg, 0.027 mmol) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(205 mg, 0.78 mmol). The reaction mixture was bubbled with N₂ for about10 mins, then microwaved at 150° C. for about 30 mins. The reactionmixture was concentrated. To the concentrated mixture were added DMSO (2mL), H₂O (0.5 mL) and AcOH (0.05 mL). Gilson with TFA provided the titlecompound as a white solid (310 mg, 99%). LC-MS m/z 483 (M+H)⁺.

Example 67 1,1-dimethylethyl3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoate(Example 111a of PU61344)

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.52 mmol) in dioxane (15 mL)/water (5 mL) were added potassiumcarbonate (433 mg, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0)(31 mg, 0.027 mmol) and(5-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-2-methylphenyl)boronicacid (159 mg, 0.63 mmol). The reaction mixture was bubbled with N₂ for10 mins, then microwaved at 150° C. for 30 mins. The reaction mixturewas concentrated. To the concentrated mixture were added DMSO (2 mL),H₂O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided thetitle compound as a white solid (270 mg, 88%). LC-MS m/z 587 (M+H)⁺.

Example 683-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzoicAcid (GSK612060A)

To the solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(191 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(197 mg, 0.75 mmol), K₂CO₃ (415 mg, 3.0 mmol) andtetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.025 mmol). Thereaction mixture was heated to 150° C. for about 15 minutes withmicrowave. The reaction mixture was concentrated to dry then was addedDMSO (2 mL), water (0.5 mL) and HOAc (1 drop). The solution was filteredand applied to the reverse phase HPLC to afford the titled compound 0.24g (quantitative). LC-MS m/z 483 (M+H)⁺; ¹H-NMR (CD₃OD) 2.36 (s, 3H),2.76 (s, 6H), 3.16 (s, 2H), 3.56 (s, 2H), 4.13 (s, 2H), 7.21 (m, 1H),7.53 (m, 2H), 7.95 (s, 1H), 8.09 (d, J=7.6 Hz, 1H).

Example 693-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethylbenzoicAcid (GSK690657A)

The title compound was prepared by following the procedure in Example 68except 3-(dihydroxyboranyl)-4-ethylbenzoic acid was used in the couplingreaction (yield: 38%). LC-MS m/z 497 (M+H)⁺; ¹H-NMR (CD₃OD) 1.22 (t,J=7.6 Hz, 3H), 2.68 (s, 2H), 2.77 (s, 6H), 3.16 (m, 2H), 3.53 (m, 2H),4.13 (m, 2H), 7.18 (m, 2H), 7.55 (m, 2H), 7.86 (s, 1H), 8.10 (m 1H).

Example 705-chloro-7-{[3-(diethylamino)propyl]amino}-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-onetrifluoroacetate (Example 228a of PU61344)

To5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(275 mg, 0.767 mmol) in dichloromethane (15 mL) was addedN,N-diethyl-1,3-propyldiamine (0.181 mL, 1.15 mmol) and triethylamine(0.215 mL, 1.53 mmol). The mixture was stirred over night. The mixturewas concentrated and separated by Gilson HPLC (with 0.1% TFA) to affordthe title compound (207 mg, 64%).

Example 713-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicAcid (GSK1229512A)

To5-chloro-7-{[3-(diethylamino)propyl]amino}-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(207 mg, 0.488 mmol) in 1,4-dioxane (7.5 mL) and water (2.5 mL) wasadded 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid (0.192 g, 0.733 mmol), tetrakis(triphenylphosphine)-palladium(0)(28.3 mg, 0.024 mmol), and potassium carbonate (270 mg, 1.95 mmol). Themixture was heated with microwave for about 15 min at 150° C., and thenallowed to cool to room temperature. The mixture was concentrated andseparated by HPLC to afford the title compound (66 mg, 26%). LC-MS m/z525 (M+H)⁺.

Example 723-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoicAcid (GSK249201A)

The solution of 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.00 mmol) in DME (150 mL) andH₂O (50 mL), in a pressure flask (500 mL, Chemglass), was added4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)benzoic acid(1.97 g, 7.50 mmol) and K₂CO₃ (4.15 g, 30.0 mmol). The resulting mixturewas degassed with Argon for 5 minutes, mixed with Pd(PPh₃)₄ (0.232 g,0.20 mmol) and heated with a preheated oil bath (160° C.) under vigorousstirring for 30 minutes. The reaction mixture was filtered throughcelite, concentrated under vacuum to remove DME. It was then mixed withEtOAc (200 mL) and AcOH (2.5 mL), and shaked. The layers were separated.The organic layer was collected, further washed with brine (70 mL),dried over Na₂SO₄, filtered, concentrated and purified via a flashchromatography (load column with DCM, mobile phase EtOAc/Hexane) toafford the title compound as a white solid 2.15 g (98%). LC-MS (ES) m/z440 (M+H)⁺; ¹H-NMR (CD₃OD) δ 2.27 (s, 3H), 2.31 (s, 3H), 6.71 (d, J=9.6Hz, 1H), 7.28 (t, J=8.2 Hz, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.64 (m, 2H),8.00 (d, J=1.6 Hz, 1H), 8.14 (dd, J₁=7.6 Hz, J₂=1.6 Hz, 1H).

Example 733-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide(GSK576970A)

4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1g, 3.8 mmoles) was taken up in CH₂Cl₂ (200 mL) and was treated withoxalyl chloride (0.44 mL, 5 mmol) and DMF (1 drop). One hour after gasevolution had ceased, the solvents were pumped off in vacuo, and theresidue stripped from toluene. This was again taken up in CH₂Cl₂ (200mL), and excess dimethyl amine was bubbled into the mixture, which wasthen sealed off and stirred overnight at room temperature. The solventswere pumped off to give the crudeN,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,which was used without further purification in the next step.

5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.102 g, 0.298 mmol),N,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidefrom above, (0.129 g, 0.447 mmol), and K₂CO₃ (0.123 g, 0.894 mmol), weretaken up in dioxane (6 mL) and water (1.2 mL). The mixture was degassedwith argon for 30 min and tetrakis(triphenyl-phosphine)palladium(0)(0.026 g, 0.022 mmol) was added. The mixture was then heated under argonat 95° C. for 18 h. The solvents were pumped off, and after aqueousworkup, the crude material was flashed on silica gel (15 g), eluted witha EtOAc/CH₂Cl₂ gradient to give the title compound as a white amorphoussolid. mp 144-147° C. LC-MS m/z 470 (M+H)⁺, 2.02 min (ret time).

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingClaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed, are defined asfollows.

1. A compound of formula (II):

wherein G1 is CH₂; G2 is CH; Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;Rg is a C₁₋₁₀ alkyl; m is 0, or an integer having a value of 1, or 2; R₃is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic or aheterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties maybe optionally substituted.
 2. The compound according to claim 1 which isFormula (II).
 3. The compound according to claim 1 which is Formula(IIa).
 4. The compound according to claim 1 wherein Rg is methyl.
 5. Thecompound according to claim 4 wherein m is
 0. 6. The compound accordingto claim 4 wherein m is
 2. 7. The compound according claim 1 wherein Rxis chloro.
 8. The compound according claim 1 wherein R₃ is an optionallysubstituted aryl.
 9. The compound according to claim 8 wherein R₃ isoptionally substituted independently, one or more times, independentlyat each occurrence by halogen, C₁₋₁₀ alkyl, hydroxy, C₁₋₁₀ alkoxy,cyano, nitro, amino, or halosubstituted C₁₋₁₀ alkyl.
 10. The compoundaccording to claim 9 wherein R₃ is a phenyl substituted one or moretimes independently by fluorine, chlorine, or methyl.
 11. The compoundaccording to claim 8 wherein R₃ is phenyl, 4-trifluoromethyl-phenyl,2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl,2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl.
 12. The compoundaccording to claim 1 which is:4-Chloro-8-(4-trifluoromethyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one;4-Chloro-8-(4-trifluoromethyl-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one;4-Chloro-8-(2,4-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one;4-Chloro-8-(2,4-difluoro-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one;4-Chloro-8-(2,6-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one;and4-Chloro-8-(2,6-difluoro-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one.13. A compound of the formula:

wherein G1 is —CH₂: G2 is CH; Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;X is R₂, OR_(2″), S(O)_(m)R_(2″), (CH₂)_(n′)N(R₁₁)S(O)_(m)R_(2′),(CH₂)_(n′)N(R₁₁)C(O)R_(2′), (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n′)N(R_(2′))(R_(2″)), or N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′; X₁is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀; R_(h) is selected from an optionallysubstituted C₁₋₁₀ alkyl, —CH₂—C(O)—CH₂—, —CH₂CH₂—O—CH₂—CH₂—,—CH₂—C(O)N(R_(10′))CH₂—CH₂—, —CH₂—N(R_(10′))C(O)CH₂—,—CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—, or —CH₂—CH₂—O—C(O)CH₂—;R_(q) and R_(q′) are independently selected at each occurrence fromhydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, wherein all of the moieties, excluding hydrogen, areoptionally substituted, or R_(q) and R_(q′) together with the nitrogento which they are attached form a 5 to 7 membered optionally substitutedring, which ring may contain an additional heteroatom selected fromoxygen, nitrogen or sulfur; R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl, arylC₁₋₁₀-alkyl, heteroaryl,heteroarylC₁₋₁₀-alkyl, heterocyclic, or a heterocyclylC₁₋₁₀-alkylmoiety, and wherein each of these moieties, excluding hydrogen, may beoptionally substituted; or R₂ is the moiety(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃); R_(2′) ishydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl,arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or aheterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties,excluding hydrogen, may be optionally substituted; R_(2″) is hydrogen,C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl,arylC₁₋₁₀-alkyl, heteroaryl, heteroarylC₁₋₁₀-alkyl, heterocyclic, or aheterocyclylC₁₋₁₀-alkyl moiety, and wherein these moieties, excludinghydrogen, may be optionally substituted; or wherein R_(2″) is the moiety(CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃); A₁ is an optionallysubstituted C₁₋₁₀ alkyl, heterocyclic, heterocyclic C₁₋₁₀ alkyl,heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl, or aryl C₁₋₁₀ alkyl; A₂ is anoptionally substituted C₁₋₁₀ alkyl, heterocyclic, heterocyclic C₁₋₁₀alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl, or aryl C₁₋₁₀ alkyl; A₃is hydrogen or is an optionally substituted C₁₋₁₀ alkyl; R₃ is a C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic or aheterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties maybe optionally substituted; R₄ and R₁₄ are each independently selectedfrom hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,aryl, aryl-C₁₋₁₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of thesemoieties, excluding hydrogen, may be optionally substituted; or the R₄and R₁₄ together with the nitrogen which they are attached form anoptionally substituted heterocyclic ring of 4 to 7 members, which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or nitrogen; R₁₀ and R₂₀ are independently selected from hydrogenor C₁₋₄alkyl; R_(10′) is independently selected at each occurrence fromhydrogen or C₁₋₄alkyl; R₁₁ is independently selected from hydrogen orC₁₋₄alkyl; n′ is independently selected at each occurrence from 0 or aninteger having a value of 1 to 10; m is independently selected at eachoccurrence from 0 or an integer having a value of 1 or 2; q is 0 or aninteger having a value of 1 to 10; q′ is 0, or an integer having a valueof 1 to 6; or t is an integer having a value of 2 to
 6. 14. The compoundaccording to claim 13 which is Formula (III).
 15. The compound accordingto claim 13 which is Formula (IIIa).
 16. The compound according to claim13 wherein Rx is chloro.
 17. The compound according to claim 13 whereinR₃ is an optionally substituted aryl.
 18. The compound according toclaim 17 wherein R₃ is optionally substituted independently, one or moretimes, independently at each occurrence by halogen, C₁₋₁₀ alkyl,hydroxy, C₁₋₁₀ alkoxy, cyano, nitro, amino, or halosubstituted C₁₋₁₀alkyl.
 19. The compound according to claim 18 wherein R₃ is phenylsubstituted one or more times independently by fluorine, chlorine ormethyl.
 20. The compound according to claim 13 wherein R₃ is phenyl,4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl,2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or2,6-dimethylphenyl.
 21. The compound according to claim 13 wherein X isR₂, and R₂ is (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), orC(A₁)(A₂)(A₃).
 22. The compound according to claim 21 wherein at leastone of A₁, A₂ or A₃ is a C₁₋₁₀ alkyl substituted by (CR₁₀R₂₀)_(n)OR₆;and wherein n is 0, or an integer having a value of 1 to 10; m is 0 oran integer having a value of 1 or 2; R₆ is independently selected fromhydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a heteroarylC₁₋₁₀ alkylmoiety, and wherein these moieties, excluding hydrogen may be optionallysubstituted independently at each occurrence, one or more times, byhalogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy;halosubstituted C₁₋₁₀ alkoxy; S(O)_(m) alkyl; C(O); NR_(4′)R_(14′);C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstitutedC₁₋₁₀ alkyl; an unsubstituted aryl or arylalkyl, or an aryl or arylalkylsubstituted one or two times by halogen, hydroxy, hydroxy substitutedalkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄alkyl amino, C₁₋₄ alkyl, or CF₃; R_(4′) and R_(14′) are eachindependently selected at each occurrence from hydrogen or C₁₋₄ alkyl,or R_(4′) and R_(14′) can cyclize together with the nitrogen to whichthey are attached to form an optionally substituted 5 to 7 membered ringwhich optionally contains an additional heteroatom selected from oxygen,sulfur or NR_(9′); and R_(9′) is independently selected at eachoccurrence from hydrogen, or C₁₋₄ alkyl.
 23. The compound according toclaim 21 wherein X₁ is N(R_(10′)), q is 0 or 1, q′ is 0, and R₆ ishydrogen.
 24. The compound according to claim 13 wherein X is(CH₂)_(n′)NR₄R₁₄, or (CH₂)_(n′)N(R_(2′))(R_(2″)).
 25. The compoundaccording to claim 24 wherein X is (CH₂)_(n′)NR₄R₁₄, and R₄ and R₁₄ areindependently selected from hydrogen, optionally substituted C₁₋₁₀alkyl, optionally substituted aryl, optionally substituted aryl-C₁₋₄alkyl, optionally substituted heterocyclic, optionally substitutedheterocylic C₁₋₄ alkyl, optionally substituted heteroaryl or optionallysubstituted heteroaryl C₁₋₄ alkyl.
 26. The compound according to claim25 wherein the C₁₋₁₀ alkyl may be substituted one or more times,independently at each occurrence with NR_(4′)R_(14′); halogen, hydroxy,alkoxy, C(O)NR_(4′)R_(14′); or NR_(4′)C(O) C₁₋₁₀alkyl; and whereinR_(4′) and R_(14′) are independently selected at each occurrence fromhydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′) together with the nitrogento which they are attached form a heterocyclic ring of 5 to 7 members,which ring optionally contains an additional heteroatom selected fromNR_(9′); and R_(9′) is independently selected at each occurrence fromhydrogen, or C₁₋₄ alkyl.
 27. The compound according to claim 24 whereinX is (CH₂)_(n′)N(R_(2′))(R_(2″)), and R_(2′) is an optionallysubstituted C₁₋₁₀ alkyl, cycloalkyl, heterocyclic, heterocyclyl C₁₋₁₀alkyl, or heteroarylalkyl.
 28. The compound according to claim 27wherein the R₂, moieties, excluding hydrogen, are optionally substituted1 to 4 times, independently, at each occurrence, by C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, aryl, aryl C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀ alkyl, heterocyclic, heterocyclic C₁₋₁₀ alkyl,heteroaryl, heteroaryl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇,(CR₁₀R₂₀)_(n)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z) NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z) NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; and wherein R₆ is independently selectedat each occurrence from hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroarylor heteroarylC₁₋₁₀ alkyl, wherein each of these moieties, excludinghydrogen are optionally substituted; R₇ is independently selected ateach occurrence from C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl moiety, andwherein each of these moieties may be optionally substituted; R_(e) areR_(e′) are each independently selected at each occurrence from hydrogen,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heteroaryl or a heteroarylC₁₋₄ alkyl moiety; or R_(e) and R_(e′) together with the nitrogen whichthey are attached form an optionally substituted heterocyclic ring of 4to 7 members, which ring optionally contains an additional heteroatomselected from oxygen, sulfur or nitrogen; and wherein each of thesemoieties, excluding hydrogen, may be substituted 1 to 4 times,independently at each occurrence by halogen; hydroxy; hydroxysubstituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy;amino, mono & di-substituted C₁₋₄ alkyl amino, S(O)_(m)R_(f); C(O)R_(j);C(O)O R_(j); (CR₁₀R₂₀)_(n)N(R₁₀)C(Z)OR₇;(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); C(O)NR_(4′)R_(14′);NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl; cyano; nitro; C₁₋₁₀ alkyl;C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl;aryl, aryl C₁₋₄ alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, heteroaryl,or heteroarylC₁₋₄alkyl, and wherein these aryl, heterocyclic, andheteroaryl containing moieties may be optionally substituted one to twotimes independently at each occurrence by halogen, C₁₋₄ alkyl, hydroxy,hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono& di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃; R_(d) and R_(d′)are each independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylC₁₋₄alkyl, or the R_(d) and R_(d′) togetherwith the nitrogen which they are attached form an optionally substitutedheterocyclic ring of 5 to 6 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR_(9′); andwherein the R_(d) and R_(d′) moieties which are C₁₋₄ alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄ alkyl, and the R₄ and R₁₄ cyclizedring are optionally substituted, 1 to 4 times, independently by halogen;halosubstituted C₁₋₄ alkyl; hydroxy; hydroxy substituted C₁₋₄alkyl; C₁₋₄alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)_(m)R_(f); C(O)R_(j); ; C(O)OR_(j); C(O)NR_(4′)R_(14′), NR_(4′)C(O)C₁₋₄alkyl;S(O)₂NR_(4′)R_(14′)OC₁₋₄ alkyl; NR_(4′)R_(14′)S(O)₂C₁₋₄ alkyl; orNR_(4′)R_(14′); R_(f) is independently selected at each occurrence fromC₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroaryl C₁₋₁₀alkyl,heterocyclic, or a heterocyclic C₁₋₁₀alkyl moiety, and wherein thesemoieties may all be optionally substituted; R_(f′) is independentlyselected at each occurrence from hydrogen, C₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroaryl C₁₋₁₀alkyl, heterocyclic,heterocyclic C₁₋₁₀alkyl, or NR_(4′)R_(14′) and wherein these moietiesmay all be optionally substituted; R_(4′) and R_(14′) are eachindependently selected at each occurrence from hydrogen or C₁₋₄ alkyl,or R_(4′) and R_(14′) can cyclize together with the nitrogen to whichthey are attached to form a 5 to 7 membered ring which optionallycontains an additional heteroatom selected from oxygen, sulfur orNR_(9′); R_(9′) is independently selected at each occurrence fromhydrogen, or C₁₋₄ alkyl; R_(j) is independently selected at eachoccurrence from hydrogen, C₁₋₄alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl,heteroaryl C₁₋₄alkyl, heterocyclic, or a heterocyclic C₁₋₄alkyl moiety,and wherein these moieties, excluding hydrogen, may be optionallysubstituted; and n is independently selected at each occurrence from 0or an integer having a value of 1 to
 10. 29. The compound according toclaim 28 wherein R_(2′) is a heterocyclic or a heterocyclic alkylsubstituted one or more times, independently by C₁₋₁₀ alkyl, aryl,arylalkyl, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), or (CR₁₀R₂₀)_(n)N(R₁₀)C(Z)OR₇. 30.The compound according to claim 13 wherein the(CH₂)_(n′)N(R_(2′))(R_(2″)) moiety is 1-(phenylmethyl)-4-piperidinamine,2-[4-(phenylmethyl)-1-piperazinyl]ethylamine,2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine,1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine,3-[(hexahydro-1H-azepin-1-yl)propyl]amine,(1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine,3-[(2-oxo-1-pyrrolidinyl)propyl]amine, 2-[(4-morpholinyl)ethyl]amine,2-[(1-pyrrolidinyl)ethyl]amine, or[(1-ethyl-2-pyrrolidinyl)methyl]amine.
 31. The compound according toclaim 13 wherein R_(2′) is a C₁₋₁₀ alkyl substituted by(CR₁₀R₂₀)_(n)NR_(e)R_(e′) or(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′); and wherein R_(e) areR_(e′) are each independently selected at each occurrence from hydrogen,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₄alkyl, aryl, aryl-C₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heteroaryl or a heteroarylC₁₋₄ alkyl moiety; or R_(e) and R_(e′) together with the nitrogen whichthey are attached form an optionally substituted heterocyclic ring of 4to 7 members, which ring optionally contains an additional heteroatomselected from oxygen, sulfur or nitrogen; and wherein each of thesemoieties, excluding hydrogen, may be substituted 1 to 4 times,independently at each occurrence by halogen; hydroxy; hydroxysubstituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy;amino, mono & di-substituted C₁₋₄ alkyl amino, S(O)_(m)R_(f′);C(O)R_(j); C(O)OR_(j); (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); C(O)NR_(4′)R_(14′);NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl; cyano; nitro; C₁₋₁₀ alkyl;C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl;aryl, aryl C₁₋₄ alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, heteroaryl,or heteroarylC₁₋₄alkyl, and wherein these aryl, heterocyclic, andheteroaryl containing moieties may be optionally substituted one to twotimes independently at each occurrence by halogen, C₁₋₄ alkyl, hydroxy,hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono& di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃; R_(d) and R_(d′)are each independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylC₁₋₄alkyl, or the R_(d) and R_(d′) togetherwith the nitrogen which they are attached form an optionally substitutedheterocyclic ring of 5 to 6 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR_(9′); andwherein the R_(d) and R_(d′) moieties which are C₁₋₄ alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄ alkyl, and the R₄ and R₁₄ cyclizedring are optionally substituted, 1 to 4 times, independently by halogen;halosubstituted C₁₋₄ alkyl; hydroxy; hydroxy substituted C₁₋₄alkyl; C₁₋₄alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)_(m)Rf, C(O)R_(j); C(O)O R_(j);C(O)NR_(4′)R_(14′)NR_(4′)C(O)C₁₋₄alkyl; S(O)₂NR_(4′)R_(14′)C₁₋₄ alkyl;NR_(4′)R_(14′)S(O)₂C₁₋₄ alkyl; or N_(4′)R_(14′); R_(f) is independentlyselected at each occurrence from C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀ alkyl,heteroaryl, heteroaryl C₁₋₁₀alkyl, heterocyclic, or a heterocyclic C₁₋₁₀alkyl moiety, and wherein these moieties may all be optionallysubstituted; R_(f′) is independently selected at each occurrence fromhydrogen, C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, heterocyclic C₁₋₁₀alkyl, or NR_(4′)R_(14′) andwherein these moieties may all be optionally substituted; R_(4′) andR_(14′) are each independently selected at each occurrence from hydrogenor C₁₋₄ alkyl, or R_(4′) and R_(14′) can cyclize together with thenitrogen to which they are attached to form a 5 to 7 membered ring whichoptionally contains an additional heteroatom selected from oxygen,sulfur or NR_(9′); R_(9′) is independently selected at each occurrencefrom hydrogen, or C₁₋₄ alkyl; Rj is independently selected at eachoccurrence from hydrogen, C₁₋₄alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl,heteroaryl C₁₋₄alkyl, heterocyclic, or a heterocyclic C₁₋₄alkyl moiety,and wherein these moieties, excluding hydrogen, may be optionallysubstituted; and n is independently selected at each occurrence from 0or an integer having a value of 1 to
 10. 32. The compound according toclaim 31 wherein R_(e) and R_(e′) are independently selected frommethyl, ethyl, isopropyl, n-butyl, or t-butyl.
 33. The compoundaccording to claim 13 wherein (CH₂)_(n′)N(R_(2′))(R_(2″)) is3-(dimethylamino)propyl(methyl)amine, 3-(diethylamino)propylamine,propylamine, (2,2-dimethylpropyl)amine, (2-hydroxypropyl)amino,2-(dimethylamino)ethylamine, 2-(dimethylamino)ethyl(methyl)amine,3-(dimethylamino)propylamine, 2-(dimethylamino)ethyl(methyl)amine,3-(diethylamino)propylamine, 2-(methylamino)ethylamine,[(1-methylethyl)amino]ethylamine, 3-(diethylamino)propylamine,3-(dibutylamino)propylamine, 3-[(1-methylethyl)amino]propylamine,3-(1,1-dimethylethyl)aminopropylamino,3-(dimethylamino)-2,2-dimethylpropylamine,4-(diethylamino)-1-methylbutylamine, or3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine.
 34. Thecompound according to claim 13 wherein R₃ is an aryl optionallysubstituted one or more times independently at each occurrence withhalogen, nitro, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl,C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₁₆R₂₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR₁₆R₂₆, (CR₁₀R₂₀)_(n)OC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)N(R_(10′))C(Z) NR₁₆R₂₆, or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; and wherein R₆ is independently selectedfrom hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or a heteroarylC₁₋₁₀ alkylmoiety, and wherein these moieties, excluding hydrogen may be optionallysubstituted; R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and whereineach of these moieties may be optionally substituted; R_(10′) isindependently selected at each occurrence from hydrogen or C₁₋₄ alkyl;R₁₀ and R₂₀ are independently selected at each occurrence from hydrogenor C₁₋₄ alkyl; R₁₆ and R₂₆ are each independently selected fromhydrogen, or C₁₋₄ alkyl; or the R₁₆ and R₂₆ together with the nitrogenwhich they are attached form an unsubstituted or substitutedheterocyclic ring of 4 to 7 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR_(9′); R_(9′) isindependently selected at each occurrence from hydrogen, or C₁₋₄ alkyl;n is independently selected at each occurrence from 0 or an integerhaving a value of 1 to 10; m is independently selected from 0 or aninteger having a value of 1 or 2; Z is independently at each occurrenceselected from oxygen or sulfur.
 35. The compound according to claim 33wherein R₃ is an optionally substituted phenyl.
 36. The compoundaccording to claim 35 wherein the optional substituents on the phenylring are independently selected at each occurrence from halogen,C₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₆, cyano, nitro, (CR₁₀R₂₀)_(n)NR₁₆R₂₆, orhalosubstituted C₁₋₁₀alkyl.
 37. The compound according claim 24 whereinthe phenyl is substituted one or more times by halogen, hydroxy, alkoxy,amino or CF₃.
 38. The compound according to claim 36 wherein R₃ isphenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl,2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or2,6-dimethylphenyl.
 39. The compound according to claim 13 which is:2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;and2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one.40. The compound according to claim 13 which is:4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one;4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one;4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one.41. The compound according to claim 2 wherein R₉ is methyl.
 42. Thecompound according to claim 3 wherein R₉ is methyl.
 43. The compoundaccording to claim 41 wherein m is
 0. 44. The compound according toclaim 42 wherein m is
 0. 45. The compound according to claim 41 whereinm is
 2. 46. The compound according to claim 42 wherein m is
 2. 47. Thecompound according claim 43 wherein Rx is chloro.
 48. The compoundaccording claim 44 wherein Rx is chloro.
 49. The compound according toclaim 47 wherein R₃ is phenyl or a phenyl substituted one or more timesindependently by fluorine, chlorine, or methyl.
 50. The compoundaccording to claim 49 wherein R₃ is phenyl, 4-trifluoromethyl-phenyl,2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl,2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl.
 51. The compoundaccording to claim 48 wherein R₃ is phenyl or a phenyl substituted oneor more times independently by fluorine, chlorine, or methyl.
 52. Thecompound according to claim 51 wherein R₃ is phenyl,4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl,2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or2,6-dimethylphenyl.
 53. The compound according to claim 14 wherein Rx ischloro.
 54. The compound according to claim 15 wherein Rx is chloro. 55.The compound according to claim 54 wherein R₃ is an optionallysubstituted aryl.
 56. The compound according to claim 55 wherein R₃ isoptionally substituted independently, one or more times, independentlyat each occurrence by halogen, C₁₋₁₀ alkyl, hydroxy, C₁₋₁₀ alkoxy,cyano, nitro, amino, or halosubstituted C₁₋₁₀ alkyl.
 57. The compoundaccording to claim 54 wherein R₃ is phenyl, or phenyl substituted one ormore times independently by fluorine, chlorine or methyl.
 58. Thecompound according to claim 54 wherein R₃ is phenyl,4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl,2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or2,6-dimethylphenyl.
 59. The compound according to claim 33 wherein Rx ischloro.
 60. The compound according to claim 59 which is Formula (III).61. The compound according to claim 59 wherein R₃ is a phenylsubstituted one or more times independently by fluorine, chlorine ormethyl.
 62. The compound according to claim 61 wherein X is2-(dimethylamino)ethylamino.
 63. The compound according to claim 13wherein X is R₂.
 64. The compound according to claim 63 wherein R₂ is anoptionally substituted heterocyclic selected from the group consistingof tetrahydropyrrole, tetrahydropyran, tetrahydrofuran,tetrahydrothiophene, aziridinyl, pyrrolinyl, pyrrolidinyl,2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzodioxol-5-yl,imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholino and thiomorpholino.
 65. Thecompound according to claim 64 wherein R₂ is an optionally substitutedone or mores times independently by an optionally substitutedheterocyclic, heterocyclic alkyl, aryl, arylalkyl, alkyl,(CR₁₀R₂₀)_(n)NR_(e)R_(e′), or (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; andwherein R_(e) are R_(e′) are each independently selected at eachoccurrence from hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₁₄ alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, heteroaryl or a heteroaryl C₁₋₄ alkyl moiety; or R_(e) andR_(e′) together with the nitrogen which they are attached form anoptionally substituted heterocyclic ring of 4 to 7 members, which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or nitrogen; and wherein each of these moieties, excludinghydrogen, may be substituted 1 to 4 times, independently at eachoccurrence by halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; amino, mono & di-substituted C₁₋₄alkyl amino, S(O)_(m)R_(f′); C(O)R_(j); C(O)OR_(j);(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′);C(O)NR_(4′)R_(14′); NR_(4′)C(O) C₁₋₁₀alkyl; NR_(4′)C(O)aryl; cyano;nitro; C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl;halosubstituted C₁₋₁₀ alkyl; aryl, aryl C₁₋₄ alkyl, heterocyclic,heterocyclicC₁₋₄ alkyl, heteroaryl, or heteroarylC₁₋₄alkyl, and whereinthese aryl, heterocyclic, and heteroaryl containing moieties may beoptionally substituted one to two times independently at each occurrenceby halogen, C₁₋₄ alkyl, hydroxy, hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀alkoxy, S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄ alkyl amino,C₁₋₄ alkyl, or CF₃; R_(d) and R_(d′) are each independently selectedfrom hydrogen, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylC₁₋₄alkyl, orthe R_(d) and R_(d′) together with the nitrogen which they are attachedform an optionally substituted heterocyclic ring of 5 to 6 members,which ring optionally contains an additional heteroatom selected fromoxygen, sulfur or NR_(9′); and wherein the R_(d) and R_(d′) moietieswhich are C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄ alkyl, and theR₄ and R₁₄ cyclized ring are optionally substituted, 1 to 4 times,independently by halogen; halosubstituted C₁₋₄ alkyl; hydroxy; hydroxysubstituted C₁₋₄alkyl; C₁₋₄ alkoxy; halosubstituted C₁₋₄ alkoxy;S(O)_(m)R_(f), C(O)R_(j); C(O)O R_(j); C(O)NR_(4′)R_(14′),NR_(4′)C(O)C₁₋₄alkyl; S(O)₂NR_(4′)R_(14′)C₁₋₄ alkyl;NR_(4′)R_(14′)S(O)₂C₁₋₄ alkyl; or NR_(4′)R_(14′); R_(f) is independentlyselected at each occurrence from C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl,heteroaryl, heteroaryl C₁₋₁₀alkyl, heterocyclic, or a heterocyclicC₁₋₁₀alkyl moiety, and wherein these moieties may all be optionallysubstituted; R_(f′) is independently selected at each occurrence fromhydrogen, C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, heterocyclic C₁₋₁₀alkyl, or NR_(4′)R_(14′) andwherein these moieties may all be optionally substituted; R_(4′) andR_(14′) are each independently selected at each occurrence from hydrogenor C₁₋₄ alkyl, or R_(4′) and R_(14′) can cyclize together with thenitrogen to which they are attached to form a 5 to 7 membered ring whichoptionally contains an additional heteroatom selected from oxygen,sulfur or NR_(9′); R_(9′) is independently selected at each occurrencefrom hydrogen, or C₁₋₄ alkyl; Rj is independently selected at eachoccurrence from hydrogen, C₁₋₄alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl,heteroaryl C₁₋₄alkyl, heterocyclic, or a heterocyclic C₁₋₄alkyl moiety,and wherein these moieties, excluding hydrogen, may be optionallysubstituted; and n is independently selected at each occurrence from 0or an integer having a value of 1 to
 10. 66. The compound according toclaim 65 wherein the R₂ optionally substituted heterocyclic is selectedfrom an optionally substituted morpholino, piperidine, or pyrrolidinyl.67. The compound according to claim 64 wherein R₂ is an optionallysubstituted piperidinyl or piperazinyl ring.
 68. The compound accordingto claim 63 wherein R₂ is a 4-amino-1-piperidinyl,1,1-dimethylethyl)oxy]-carbonyl}amino)-1-piperidinyl,4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl,4-butyl-1-piperazinyl, 4-(methylamino)-1-piperidinyl,1,1-dimethylethyl-4-piperidinyl}methylcarbamate, 4-phenyl-1-piperazinyl,1,4′-bipiperidin-1′-yl, 4-(1-pyrrolidinyl)-1-piperidinyl,4-methyl-1,4′-bipiperidin-1′-yl, 4-(4-morpholinyl)-1-piperidinyl,4-(diphenylmethyl)-1-piperazinyl, or4-methylhexahydro-1H-1,4-diazepin-1-yl.
 69. The compound according toclaim 68 wherein R₂ is 4-methyl-1,4′-bipiperidin-1′-yl, or(1-pyrrolidinyl)-1-piperidinyl.